TW201536306A - Traditional chinese medicine composition, and preparation and application thereof - Google Patents

Traditional chinese medicine composition, and preparation and application thereof Download PDF

Info

Publication number
TW201536306A
TW201536306A TW103124002A TW103124002A TW201536306A TW 201536306 A TW201536306 A TW 201536306A TW 103124002 A TW103124002 A TW 103124002A TW 103124002 A TW103124002 A TW 103124002A TW 201536306 A TW201536306 A TW 201536306A
Authority
TW
Taiwan
Prior art keywords
dropping
peg
chinese medicine
medicine composition
traditional chinese
Prior art date
Application number
TW103124002A
Other languages
Chinese (zh)
Other versions
TWI631956B (en
Inventor
Xi-Jun Yan
Nai-Feng Wu
Kai-Jing Yan
Zheng-Liang Ye
shun-nan Zhang
li-hong Zhou
wen-sheng Zhang
hai-ou Dong
Original Assignee
Tasly Pharmaceutical Group Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tasly Pharmaceutical Group Co filed Critical Tasly Pharmaceutical Group Co
Publication of TW201536306A publication Critical patent/TW201536306A/en
Application granted granted Critical
Publication of TWI631956B publication Critical patent/TWI631956B/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/82—Theaceae (Tea family), e.g. camellia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2893—Tablet coating processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Botany (AREA)
  • Medical Informatics (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Emergency Medicine (AREA)
  • Zoology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hematology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A traditional Chinese medicine composition for treating cardiovascular disease, and a preparation thereof, particularly a micro drop pill preparation thereof, and a method for preparing the preparation; the method for preparing the micro drop pill preparation can be used to prepare drop pills, coated drop pills, and drop pill capsules with a high drug loading capacity.

Description

中藥組合物及其製劑和用途 Traditional Chinese medicine composition, preparation and use thereof

本發明涉及一種中藥組合物及其製劑，具體而言，本發明涉及具有心血管治療作用的中藥組合物及其製劑、特別是其微滴丸製劑，本發明還涉及所述中藥組合物及其製劑的製備方法，其中，本發明的微滴丸製劑製備工藝可用於製備高載藥量滴丸、包衣滴丸以及滴丸膠囊。 The present invention relates to a traditional Chinese medicine composition and a preparation thereof, and in particular to a traditional Chinese medicine composition having a cardiovascular therapeutic effect and a preparation thereof, particularly a micropellet preparation thereof, and to the traditional Chinese medicine composition and the same The preparation method of the preparation, wherein the preparation method of the micro-drop pellet preparation of the invention can be used for preparing a high-load-dose dropping pill, a coating dripping pill and a dropping pill capsule.

隨著生活水準的提高、世界人口老齡化及發病群體的年輕化，心腦血管患者逐年增加，已經成為危害人類健康的第二大疾病。心絞痛是一種由心肌暫時缺血、缺氧所引起的，以發作性胸痛或胸部不適為主要表現的臨床綜合症。冠心病心絞痛是指由於冠狀動脈硬化或痙攣導致心肌缺血、缺氧所引起的心絞痛，約占心絞痛患者的90%。 With the improvement of living standards, the aging of the world population and the rejuvenation of the diseased population, the number of cardiovascular and cerebrovascular patients has increased year by year, and it has become the second most serious disease endangering human health. Angina pectoris is a clinical syndrome caused by temporary myocardial ischemia and hypoxia, with epileptic chest pain or chest discomfort as the main manifestation. Coronary heart disease angina pectoris refers to angina caused by myocardial ischemia and hypoxia due to coronary arteriosclerosis or spasm, accounting for about 90% of patients with angina pectoris.

目前治療心絞痛的方法以擴張血管、降低血黏度、抗血小板凝聚、抗凝血為主。應用的傳統西藥為硝酸酯、亞硝酸酯類、β-受體阻滯劑、鈣拮抗劑等，但是均存在較大的毒副作用，不宜長期服用，多為症狀性的治療而對病程進展無較大作用。例如服用***後有時會出現頭脹、頭內跳動、心跳加快，甚至昏厥[參見新編藥物學(第14版)264頁]，近年來又發現有致嚴重低血壓[參見中國現代醫學雜誌，1997，7(4)：42；陝西醫學雜誌，1996，25(5)：315]、易產生耐受性[參見南方護理雜誌1996，3(5)：7~9]等問題，阻礙了其在臨床上的應用。 At present, the method for treating angina pectoris is to dilate blood vessels, reduce blood viscosity, resist platelet aggregation, and resist blood coagulation. The traditional western medicines used are nitrates, nitrites, β-blockers, calcium antagonists, etc., but all have large toxic side effects, which are not suitable for long-term use, mostly symptomatic treatment and no progress on the course of the disease. Great effect. For example, after taking nitroglycerin, there may be head swelling, head jumping, rapid heartbeat, and even fainting [see New Pharmacy (14th Edition), page 264]. In recent years, it has been found to cause severe hypotension [see Chinese Journal of Modern Medicine, 1997, 7 (4): 42; Shaanxi Medical Journal, 1996, 25 (5): 315], easy to produce tolerance [see Southern Care Journal 1996, 3 (5): 7 ~ 9] and other issues, hindering its In clinical application.

雖然亦有不少治療心絞痛的中成藥，其中丸、散、膏、丹、湯劑早已成為古老的歷史，現代人極少應用。目前市場上有普通 複方丹參片和膠囊等製劑出售，但普通片劑、膠囊生產工藝落後，有效成分含量低，無品質控制指標，需口服經胃腸道吸收，在肝臟發生首過效應後吸收入血，生物利用度低，吸收慢，並不能適合心絞痛患者的急救之需。 Although there are many proprietary Chinese medicines for treating angina pectoris, pills, powder, cream, dan and decoction have long been an ancient history, and modern people rarely use it. Currently on the market Compound Danshen tablets and capsules are sold, but the production process of ordinary tablets and capsules is backward, the content of active ingredients is low, there is no quality control index, it needs oral absorption through the gastrointestinal tract, and it is absorbed into the blood after the first pass effect of the liver. Bioavailability Low, slow absorption, and can not be suitable for the first aid needs of patients with angina.

滴丸是中藥製劑的傳統劑型，它的優點在於：能減小藥物揮發、增加藥物穩定性、生物利用率高、起效迅速、局部給藥有長效作用、生產週期短、無粉塵污染且便於攜帶和貯存。 Dropping pills are traditional dosage forms of traditional Chinese medicine preparations. They have the advantages of reducing drug volatilization, increasing drug stability, high bioavailability, rapid onset, long-acting effects on local administration, short production cycle, and no dust pollution. Easy to carry and store.

但傳統滴丸的製備工藝是將熔融藥液滴至與其不相混溶的冷卻介質中，由於主要依靠下落重力、藥液表面張力及內應力的作用成形，所以基質的使用量大、單位載藥量小(主藥載藥量一般僅在25%左右)，不符合國際市場對於PEG類輔料每日最高服用劑量不超過700mg的限制，無法滿足國際市場要求。而且，傳統滴丸工藝很難做到小於2.5mm粒徑的滴丸，患者每次需要服用大量不易吞咽的藥丸，不適應現代快節奏的要求，也容易出現劑量不准等問題，不易為國際市場消費者普遍接受。滴製頻次較低、圓度不夠、丸重及滴丸大小差異較大，為保證滴製效果需加入大量的基質，導致單位載藥量小、服藥量較大；使用冷卻液凝固滴丸，需加入後期除油工序，且會有冷卻液無法除盡而帶來的有機溶劑殘留問題。用傳統滴丸乾燥方法，時間長、速度慢、乾燥不均勻，容易造成含揮發油產品的揮發、或含冰片產品在乾燥過程中析出冰片等問題。 However, the preparation process of the traditional dropping pills is to drop the molten medicine into a cooling medium which is immiscible with it, and is mainly formed by the action of falling gravity, surface tension of the liquid and internal stress, so that the amount of the substrate is large and the unit load is large. The dosage is small (the main drug loading is generally only about 25%), which does not meet the international market limit for the maximum daily dose of PEG excipients not exceeding 700mg, which cannot meet the requirements of the international market. Moreover, the traditional dropping pill process is difficult to achieve a dropping pill of less than 2.5 mm in diameter. The patient needs to take a large number of pills that are not easy to swallow each time, which is not suitable for the requirements of modern fast-paced, and is also prone to problems such as inaccurate dosage, and is not easy for international Market consumers generally accept. The frequency of dropping is low, the roundness is not enough, the weight of the pill and the size of the dropping pill are large. To ensure the dripping effect, a large amount of matrix is needed, resulting in a small drug loading amount and a large dosage; It is necessary to add a post-oil removal process, and there is a problem of residual organic solvent caused by the inability of the coolant to be removed. With the traditional dropping method, the time is long, the speed is slow, and the drying is uneven, which may easily cause the volatilization of the volatile oil-containing product or the precipitation of borneol in the drying process of the borneol product.

因此，如何找到一種能夠有效增加生產速率、降低基質使用量、提高載藥量、能製備小粒徑滴丸、同時具備製備普通滴丸劑及滴丸膠囊能力的生產工藝，是現代滴丸製備工藝需要發展和探索的重要課題。 Therefore, how to find a production process capable of effectively increasing the production rate, reducing the amount of substrate used, increasing the drug loading amount, preparing small particle size dropping pills, and having the ability to prepare ordinary dropping pills and dropping pills, is a modern dropping pill preparation process. Important topics that need to be developed and explored.

複方丹參滴丸為天士力公司開發的活血化瘀、理氣止痛的中藥，用於胸中憋悶、心絞痛，其主要成分為丹參、三七和冰片，其藥理作用包括：增加冠脈血流量；增加心肌耐缺氧、保護缺血 心肌；抗血小板聚集、防止血栓形成；以及改善微循環。儘管先前技術對於複方丹參滴丸的製備已經非常成熟，但在製備過程中仍然面臨上面所提及的基質的使用量大、單位載藥量小等問題。 Compound Danshen Dripping Pill is a traditional Chinese medicine for promoting blood circulation, relieving qi and relieving pain developed by Tianshili Company. It is used for chest pain and angina pectoris. Its main components are Danshen, Sanqi and Borneol. Its pharmacological effects include: increasing coronary blood flow and increasing myocardial resistance. Hypoxia, protection of ischemia Myocardium; anti-platelet aggregation, prevention of thrombosis; and improved microcirculation. Although the prior art has been very mature for the preparation of the compound Danshen dropping pills, it still faces problems such as the use amount of the substrate mentioned above and the small drug loading amount in the preparation process.

本發明的目的是提供一種具有治療急性心肌梗塞和急性心肌缺血作用的中藥組合物，所述中藥組合物是由以重量百分比計的丹參三七提取物50.0%~99.9%和冰片0.1%~50.0%組成的，其中，所述丹參三七提取物含有以下組分，各組分的重量比為：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(2~6)：(0.5~2)：(1~3)：(0.2~1)：(0.2~1)：(0.5~2)：(0.5~2)：(0.2~1)：(1~4)：(0.1~0.5)：(1~4)：(0.1~1)：(0.01~0.05)：(0.05~0.1)：(0.02~0.1)：(0.1~0.5)。 The object of the present invention is to provide a traditional Chinese medicine composition for treating acute myocardial infarction and acute myocardial ischemia, which comprises 50.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% of borneol in weight percentage. The composition of 50.0%, wherein the extract of Salvia miltiorrhiza Bge. contains the following components, and the weight ratio of each component is: Danshensu: salvianolic acid T: protocatechuic aldehyde: salvianolic acid D: rosmarinic acid: Salvianolic acid B: salvianolic acid A: notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginsenoside Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = (2~6) :(0.5~2):(1~3):(0.2~1):(0.2~1):(0.5~2):(0.5~2):(0.2~1):(1~4):( 0.1~0.5): (1~4): (0.1~1): (0.01~0.05): (0.05~0.1): (0.02~0.1): (0.1~0.5).

本發明所述的中藥組合物可以製成各種製劑，例如：注射劑、片劑、膠囊劑、滴丸及微滴丸等，優選微滴丸劑。所述“微滴丸”是指和現有的滴丸相比，體積更小的滴丸。具體而言，是指粒徑為0.2mm~4mm的滴丸，特別是指粒徑為0.2mm~2mm、優選粒徑為1mm~2mm的滴丸。 The traditional Chinese medicine composition of the present invention can be prepared into various preparations, for example, injections, tablets, capsules, dropping pills, and microdroplets, and the like, preferably a micropellet. The "microdroplet pellet" refers to a smaller volume of pellets than the existing pellets. Specifically, it means a dropping pellet having a particle diameter of 0.2 mm to 4 mm, and particularly refers to a dropping pellet having a particle diameter of 0.2 mm to 2 mm and preferably a particle diameter of 1 mm to 2 mm.

本發明的另一目的是提供一種複方丹參微滴丸，在所述微滴丸中，藥物與基質的重量比為1：5~5：1，微滴丸的粒徑為0.2mm~4mm，並且，所述微滴丸的製備方法包括如下步驟：化料步驟：藥物與滴丸基質加熱熔融，得到熔融藥液。 Another object of the present invention is to provide a compound Danshen microdroplet in which the weight ratio of the drug to the matrix is 1:5 to 5:1, and the particle size of the microdroplet is 0.2 mm to 4 mm. Moreover, the preparation method of the micropellet comprises the following steps: a chemical step: heating and melting the drug and the dropping matrix to obtain a molten chemical.

滴製步驟：將所述熔融藥液輸送到滴頭，通過振動滴製法使所述熔融藥液滴出。 Driping step: The molten chemical is delivered to a dripper, and the molten drug is dropped by a vibration dropping method.

冷凝步驟：滴出的藥滴經過冷卻氣體冷卻，得到微滴丸。 Condensation step: The dripped drops are cooled by a cooling gas to obtain microdroplets.

具體而言，本發明包括如下技術方案： Specifically, the present invention includes the following technical solutions:

1.一種中藥組合物，所述中藥組合物是由以重量百分比計的丹參三七提取物50.0%~99.9%和冰片0.1%~50.0%組成的，其中，所述丹參三七提取物含有以下組分，各組分的重量比為：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(2~6)：(0.5~2)：(1~3)：(0.2~1)：(0.2~1)：(0.5~2)：(0.5~2)：(0.2~1)：(1~4)：(0.1~0.5)：(1~4)：(0.1~1)：(0.01~0.05)：(0.05~0.1)：(0.02~0.1)：(0.1~0.5)。 A traditional Chinese medicine composition comprising: 50.0% to 99.9% of Salvia miltiorrhiza extract, and 0.1% to 50.0% of borneol, wherein the extract of Salvia miltiorrhiza contains the following The weight ratio of the components and components is: Danshensu: Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Notoginsenoside R1: Ginseng Saponin Rg1: ginsenoside Re: ginsenoside Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = (2~6): (0.5~2): (1~3): (0.2~ 1): (0.2~1): (0.5~2): (0.5~2): (0.2~1): (1~4): (0.1~0.5): (1~4): (0.1~1) : (0.01~0.05): (0.05~0.1): (0.02~0.1): (0.1~0.5).

2.如段落1所述的中藥組合物，其中，所述中藥組合物是由以重量百分比計的丹參三七提取物75.0%~99.9%和冰片0.1%~25.0%組成的。 2. The traditional Chinese medicine composition according to paragraph 1, wherein the traditional Chinese medicine composition is composed of 75.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 25.0% of borneol.

3.如段落1所述的中藥組合物，其中，所述中藥組合物是由以重量百分比計的丹參三七提取物90.0%~99.9%和冰片0.1%~10.0%組成的。 3. The traditional Chinese medicine composition according to paragraph 1, wherein the traditional Chinese medicine composition is composed of a weight percentage of 90.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 10.0% of borneol.

4.如段落1-3中任意一項所述的中藥組合物，其中，所述丹參三七提取物含有以下組分，各組分的重量比為：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(3~4)：(0.9~1.2)：(1.4~2.0)：(0.5~0.7)：(0.5~0.9)：(1~1.6)：(0.7~1.2)：(0.5~0.9)：(1.8~2.8)：(0.2~0.4)：(1.7~2.2)：(0.2~0.6)：(0.03~0.04)：(0.07~0.08)：(0.05~0.06)：(0.26~0.28)。 4. The traditional Chinese medicine composition according to any one of paragraphs 1 to 3, wherein the extract of Salvia miltiorrhiza Bge. contains the following components, and the weight ratio of each component is: Danshensu: Salvianolic acid T: Original Tea aldehyde: salvianolic acid D: rosmarinic acid: salvianolic acid B: salvianolic acid A: notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginsenoside Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA=(3~4): (0.9~1.2): (1.4~2.0): (0.5~0.7): (0.5~0.9): (1~1.6): (0.7~1.2): (0.5~0.9): (1.8~2.8): (0.2~0.4): (1.7~2.2): (0.2~0.6): (0.03~0.04): (0.07~0.08): (0.05~0.06): (0.26 ~0.28).

5.如段落4所述的中藥組合物，其中，所述丹參三七提取物含有以下組分，各組分的重量比為：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸 B：丹酚酸A；三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=3.6：1.1：1.7：0.6：0.7：1.3：0.9：0.7：2.4：0.3：1.8：0.4：0.03：0.07：0.06：0.27。 5. The traditional Chinese medicine composition according to paragraph 4, wherein the extract of Salvia miltiorrhiza Bge. contains the following components, and the weight ratio of each component is: Danshensu: salvianolic acid T: protocatechuic aldehyde: salvianolic acid D: rosmarinic acid: salvianolic acid B: salvianolic acid A; notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginsenoside Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = 3.6:1.1:1.7:0.6: 0.7:1.3:0.9:0.7:2.4:0.3:1.8:0.4:0.03:0.07:0.06:0.27.

6.如段落1-3中任意一項所述的中藥組合物，其中，所述丹參三七提取物是由原材料按以下重量份製備得到的：丹參75~90份、三七10~25份。 6. The traditional Chinese medicine composition according to any one of paragraphs 1 to 3, wherein the extract of Salvia miltiorrhiza Bge. is prepared from the raw materials in the following parts by weight: 75-90 parts of Salvia miltiorrhiza and 10-25 parts of Sanqi .

7.如段落6所述的中藥組合物，其中，所述丹參三七提取物是由原材料按以下重量份製備得到的：丹參82~84份、三七16~17份。 7. The traditional Chinese medicine composition according to paragraph 6, wherein the extract of Salvia miltiorrhiza Bge. is prepared from the raw materials in the following parts by weight: 82-84 parts of Danshen and 16-17 parts of Sanqi.

8.一種藥物製劑，所述製劑包含段落1-7中任意一項所述的中藥組合物及藥學上可接受的載體。 A pharmaceutical preparation comprising the traditional Chinese medicine composition according to any one of paragraphs 1 to 7 and a pharmaceutically acceptable carrier.

9.如段落8所述的藥物製劑，其中，所述藥物製劑為滴丸劑或微滴丸劑，優選微滴丸劑，所述微滴丸劑是由中藥組合物與滴丸基質按照重量比1：5~5：1製成的。 9. The pharmaceutical preparation according to paragraph 8, wherein the pharmaceutical preparation is a pill or a micropellet, preferably a micropellet, which is a 1:5 by weight ratio of the traditional Chinese medicine composition to the dropping matrix. ~5:1 made.

10.一種複方丹參微滴丸劑，其中，所述複方丹參微滴丸是由重量比為1：5~5：1的中藥組合物與滴丸基質製成，所述中藥組合物是段落1-7中任一項所述的中藥組合物。 10. A compound Danshen microdroplet pellet, wherein the compound Danshen microdroplet pellet is made of a traditional Chinese medicine composition and a dropping pellet matrix in a weight ratio of 1:5 to 5:1, the Chinese medicine composition is paragraph 1 A traditional Chinese medicine composition according to any one of the preceding claims.

11.段落10所述的微滴丸劑的製備方法，所述方法包括以下步驟： 11. The method of preparing a micropellet according to paragraph 10, the method comprising the steps of:

(1)化料步驟：將藥物與滴丸基質投入均質機中，以1000~5000rpm均質混合，時間1~200min，然後，以3000~10000rpm均質化料，時間1~100min，在化料過程中，溫度保持在60~100℃，得熔融藥液，所述藥物與所述滴丸基質的重量比為1：5~5：1。 (1) Chemical step: Put the drug and the dropping pill into the homogenizer, mix homogeneously at 1000~5000rpm for 1~200min, then homogenize the material at 3000~10000rpm for 1~100min, during the chemical process. The temperature is maintained at 60 to 100 ° C to obtain a molten chemical solution, and the weight ratio of the drug to the dropping pill matrix is 1:5 to 5:1.

(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度70~300℃、滴製振動頻率2~2000Hz、滴製壓力0.5~4.0Bar、加速度1~20G的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料 速度匹配。 (2) Drip step: the above molten liquid is transported to the dripper, under the conditions of a dripper temperature of 70 to 300 ° C, a dropping vibration frequency of 2 to 2000 Hz, a dropping pressure of 0.5 to 4.0 Bar, and an acceleration of 1 to 20 G, Vibrating drop by dripper, dripping speed and step (1) chemical Speed matching.

(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm~4.0mm固態滴丸，所述冷卻氣體的溫度為0℃以下。 (3) Condensation step: The dripped drug droplet is rapidly cooled in a cooling gas to be solidified into a solid drop pellet having a particle diameter of 0.2 mm to 4.0 mm, and the temperature of the cooling gas is 0 ° C or less.

12.如段落11所述的製備方法，其中，上述步驟(1)中，所述滴丸基質包括PEG類、山梨醇、木糖醇、乳糖醇、麥芽糖、澱粉、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、***膠、海藻酸、糊精、環糊精、瓊脂、乳糖中的一種或多種組合；優選的滴丸基質為固體PEG，例如PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-5000、PEG-6000、PEG-7000、PEG-8000，進一步優選PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-6000、PEG-8000中的一種或多種組合，最優選為PEG-6000、PEG-4000或PEG-4000和PEG-6000的組合。 12. The preparation method according to paragraph 11, wherein in the above step (1), the dropping matrix comprises PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, carboxymethyl One or more combinations of sodium cellulose, hydroxypropyl methylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, lactose; a preferred dropping matrix is a solid PEG, such as PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000, PEG-8000, further preferably PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000, One or more combinations of PEG-8000 are most preferably PEG-6000, PEG-4000 or a combination of PEG-4000 and PEG-6000.

13.如段落11或12所述的製備方法，其中，所述方法包括如下步驟： 13. The method of preparation of paragraph 11 or 12, wherein the method comprises the steps of:

(1)化料步驟：將藥物與滴丸基質投入均質機中，以1000~5000rpm均質混合，然後，以3000~10000rpm均質化料，時間20~80min，在化料過程中，溫度保持在80~100℃，得熔融藥液，所述藥物與所述滴丸基質的重量比為1：3~3：1。 (1) Chemical step: put the drug and the dropping pill into the homogenizer, mix homogeneously at 1000~5000rpm, then homogenize the material at 3000~10000rpm for 20~80min, and keep the temperature at 80 during the chemical process. ~100 ° C, a molten liquid solution is obtained, and the weight ratio of the drug to the dropping pill matrix is 1:3 to 3:1.

(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度70~200℃、滴製振動頻率20~300Hz、滴製壓力0.5~4.0Bar、加速度1~15G的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配。 (2) Driping step: conveying the above molten liquid to the dripper, under the condition of a dripper temperature of 70-200 ° C, a dropping vibration frequency of 20-300 Hz, a dropping pressure of 0.5-4.0 Bar, and an acceleration of 1-15 G, The dropping speed is matched with the speed of the step (1) by the drip shaking.

(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm~4.0mm固態滴丸，所述冷卻氣體的溫度為0℃以下。 (3) Condensation step: The dripped drug droplet is rapidly cooled in a cooling gas to be solidified into a solid drop pellet having a particle diameter of 0.2 mm to 4.0 mm, and the temperature of the cooling gas is 0 ° C or less.

14.如段落12所述的製備方法，其中，上述步驟(1)中，所述藥物與所述滴丸基質的重量比為1：3~3：1，以3000~5000rpm均質混合，時間10~60min，然後，以4000~9000rpm均質化料，時間5~30min，在化料過程中，溫度保持在70~90℃；優選所述藥 物與所述滴丸基質的重量比為1：(1~3)，以3000~4000rpm均質混合，時間10~30min，然後，以4000~6000rpm均質化料，時間6~30min，在化料過程中，溫度保持在75~85℃。 14. The preparation method according to paragraph 12, wherein in the above step (1), the weight ratio of the drug to the dropping matrix is 1:3 to 3:1, and the mixture is homogeneously mixed at 3000 to 5000 rpm, time 10 ~60min, then, homogenize the material at 4000~9000rpm for 5~30min, during the process, the temperature is maintained at 70~90°C; preferably the drug The weight ratio of the substance to the dropping pill matrix is 1: (1~3), homogeneously mixed at 3000~4000 rpm for 10~30 min, then homogenized with 4000~6000 rpm, time 6~30 min, in the chemical process Medium, the temperature is maintained at 75~85 °C.

15.如段落12所述的製備方法，其中，上述步驟(2)中，滴頭溫度為70~100℃、優選75~85℃；滴製振動頻率為50~300Hz、優選100~200Hz、更優選90~200Hz、更優選130~140Hz、最優選137Hz；加速度3.5~4.5G、優選4.0G；滴製壓力為1.0~3.0Bar、優選1.8Bar；滴製速度為10~40kg/h，優選12~30kg/h，進一步優選15~25kg/h。 15. The preparation method according to paragraph 12, wherein in the step (2), the dripper temperature is 70 to 100 ° C, preferably 75 to 85 ° C; the dropping vibration frequency is 50 to 300 Hz, preferably 100 to 200 Hz, and more. Preferably, it is 90 to 200 Hz, more preferably 130 to 140 Hz, most preferably 137 Hz; acceleration is 3.5 to 4.5 G, preferably 4.0 G; the dropping pressure is 1.0 to 3.0 Bar, preferably 1.8 Bar; and the dropping speed is 10 to 40 kg/h, preferably 12 ~30 kg/h, further preferably 15 to 25 kg/h.

16.如段落12所述的製備方法，其中，上述步驟(3)中，所述氣體為空氣、氮氣、惰性氣體；冷卻溫度為0~-150℃、優選-60~-140℃、更優選-80~-120℃；所述滴丸的直徑為1.0mm~2.0mm。 16. The preparation method according to paragraph 12, wherein in the step (3), the gas is air, nitrogen, or an inert gas; the cooling temperature is 0 to -150 ° C, preferably -60 to -140 ° C, more preferably -80~-120 ° C; the diameter of the dropping pills is 1.0 mm to 2.0 mm.

17.如段落11~16中任一項所述的製備方法，其中，所述製備方法還包括作為步驟(4)的乾燥步驟，採用流化乾燥設備乾燥，在-20~100℃、優選-20~90℃乾燥1~4h，得素丸。 The preparation method according to any one of the preceding paragraphs, wherein the preparation method further comprises drying as a drying step of the step (4), using a fluidized drying apparatus, at -20 to 100 ° C, preferably - Dry at 20~90 °C for 1~4h, get the pill.

18.如段落17中任一項所述的製備方法，其中，經步驟(3)完成滴製後的低溫滴丸，經過溫度40~150℃、優選溫度40~60℃的流化床乾燥，乾燥時間1~4h、優選1~3h、最優選為2h，得素丸。 The preparation method according to any one of the preceding paragraphs, wherein the low temperature dropping pills after the completion of the dropping in step (3) are dried by a fluidized bed having a temperature of 40 to 150 ° C, preferably a temperature of 40 to 60 ° C, The drying time is 1 to 4 hours, preferably 1 to 3 hours, and most preferably 2 hours.

19.如段落18所述的製備方法，其中，所述步驟(4)採用梯度升溫乾燥法：於-20~30℃形成流化態，於15~35℃乾燥10~120min，於35~55℃乾燥10~60min，於55~100℃乾燥0~60min；優選地，所述梯度升溫乾燥法如下進行：於0~20℃形成流化態，於25℃乾燥60min，於45℃乾燥30min，於55℃乾燥0~30min。 19. The preparation method according to paragraph 18, wherein the step (4) adopts a gradient heating method: forming a fluidized state at -20 to 30 ° C, and drying at 15 to 35 ° C for 10 to 120 minutes, at 35 to 55 Drying at °C for 10~60min, drying at 55~100°C for 0~60min; preferably, the gradient heating method is carried out as follows: forming a fluidized state at 0~20°C, drying at 25°C for 60min, drying at 45°C for 30min, Dry at 55 ° C for 0 ~ 30min.

20.如段落11~19中任一項所述的製備方法，其中，所述製備方法還包括作為步驟(5)的包衣步驟，所述步驟是在所述步驟(4)得到的素丸處於流化狀態下，在30~65℃溫度下對所述素丸進行包衣；包衣液濃度為5~25wt%，優選18~20wt%，其中，包衣材料選自：蟲膠、苯二甲酸醋酸纖維素、丙烯酸甲酯、甲基丙烯 酸甲酯或歐巴代；所述包衣材料與素丸的重量比為1：50~1：10、優選1：50~1：25。 The production method according to any one of paragraphs 11 to 19, wherein the preparation method further comprises a coating step as the step (5), the step being the granule obtained in the step (4) In a fluidized state, the pill is coated at a temperature of 30 to 65 ° C; the concentration of the coating liquid is 5 to 25 wt%, preferably 18 to 20 wt%, wherein the coating material is selected from the group consisting of: shellac, benzene Cellulose acetate dicarboxylate, methyl acrylate, methacryl Methyl ester or Opadry; the weight ratio of the coating material to the pill is from 1:50 to 1:10, preferably from 1:50 to 1:25.

21.如段落11~20任一項所述的製備方法，其中，所述製備方法在步驟(1)前，還可以具有物料預混步驟，將所述藥物浸膏或粉末加水後，於30~80℃攪拌10min以上，得到藥物預混料。 The preparation method according to any one of paragraphs 11 to 20, wherein the preparation method may further comprise a material pre-mixing step, after the step (1), adding the water to the drug extract or powder, at 30 Stir at ~80 ° C for more than 10 min to obtain a drug premix.

22.段落1-7所述的中藥組合物在製備治療急性心肌梗塞和急性心肌缺血的藥物中的應用。 22. Use of the traditional Chinese medicine composition of paragraphs 1-7 for the preparation of a medicament for the treatment of acute myocardial infarction and acute myocardial ischemia.

圖1為丹酚酸T的高分辨質譜圖，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 1 is a high resolution mass spectrum of salvianolic acid T, A: (R) - salvianolic acid T; B: (S) - salvianolic acid T.

圖2為丹酚酸T的1H-NMR圖(500MHz,DMSO)，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 2 is a 1 H-NMR chart of salvianolic acid T (500 MHz, DMSO), A: (R)-salvianolic acid T; B: (S)-salvian acid T.

圖3為丹酚酸T的13C-NMR圖(125MHz,DMSO)，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 3 is a 13C-NMR chart of salvianolic acid T (125 MHz, DMSO), A: (R)-salvianolic acid T; B: (S)-salvianolic acid T.

圖4為丹酚酸T的DEPT譜，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 4 is the DEPT spectrum of salvianolic acid T, A: (R) - salvianolic acid T; B: (S) - salvianolic acid T.

圖5為丹酚酸T的COSY譜，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 5 is a COSY spectrum of salvianolic acid T, A: (R) - salvianolic acid T; B: (S) - salvianolic acid T.

圖6為丹酚酸T的ROESY譜，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 6 is a ROESY spectrum of salvianolic acid T, A: (R) - salvianolic acid T; B: (S) - salvianolic acid T.

圖7為丹酚酸T的HSQC譜，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 7 is the HSQC spectrum of salvianolic acid T, A: (R) - salvianolic acid T; B: (S) - salvianolic acid T.

圖8為丹酚酸T的HMBC譜，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 8 is the HMBC spectrum of salvianolic acid T, A: (R) - salvianolic acid T; B: (S) - salvianolic acid T.

圖9為丹酚酸T的CD譜，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 9 is a CD spectrum of salvianolic acid T, A: (R)-salvianolic acid T; B: (S)-salvianolic acid T.

圖10為丹酚酸T的CD譜與ECD模擬譜對照，A：(R)-丹酚酸T；B：(S)-丹酚酸T。 Figure 10 is a comparison of the CD spectrum of salvianolic acid T with the ECD mimetic spectrum, A: (R)-salvianolic acid T; B: (S)-salvianolic acid T.

圖11為酚酸類和丹參酮類色譜圖(檢測波長281nm)。 Figure 11 is a chromatogram of phenolic acids and tanshinones (detection wavelength 281 nm).

圖12為皂苷類色譜圖。 Figure 12 is a chromatogram of saponins.

在一個實施方式中，本發明提供一種中藥組合物。所述中藥組合物是由以重量百分比計的丹參三七提取物50.0%~99.9%、冰片0.1%~50.0%組成的，其中，所述丹參三七提取物含有(重量份)：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(2~6)：(0.5~2)：(1~3)：(0.2~1)：(0.2~1)：(0.5~2)：(0.5~2)：(0.2~1)：(1~4)：(0.1~0.5)：(1~4)：(0.1~1)：(0.01~0.05)：(0.05~0.1)：(0.02~0.1)：(0.1~0.5)。 In one embodiment, the invention provides a traditional Chinese medicine composition. The traditional Chinese medicine composition is composed of 50.0% to 99.9% of Salvia miltiorrhiza extract, 0.1% to 50.0% of borneol, wherein the extract of Salvia miltiorrhiza contains (parts by weight): Danshensu: Salvianolic acid T: protocatechuic aldehyde: salvianolic acid D: rosmarinic acid: salvianolic acid B: salvianolic acid A: notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginsenoside Rb1: ginsenoside Rd : Dihydrotanshinone I: Tanshinone I: Cryptotanshinone: Tanshinone IIA=(2~6): (0.5~2): (1~3): (0.2~1): (0.2~1): (0.5~2) :(0.5~2):(0.2~1):(1~4):(0.1~0.5):(1~4):(0.1~1):(0.01~0.05):(0.05~0.1):( 0.02~0.1): (0.1~0.5).

本發明優選的中藥組合物是由以重量百分比計的丹參三七提取物75.0%~99.9%、冰片0.1%~25.0%組成的。 The preferred traditional Chinese medicine composition of the present invention is composed of 75.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 25.0% of borneol.

本發明進一步優選的中藥組合物是由以重量百分比計的丹參三七提取物90.0%~99.9%、冰片0.1%~10.0%組成的。 A further preferred traditional Chinese medicine composition of the present invention is composed of 70.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 10.0% of borneol.

在上述中藥組合物中，所述丹參三七提取物優選含有(重量份)：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(3~4)：(0.9~1.2)：(1.4~2.0)：(0.5~0.7)：(0.5~0.9)：(1~1.6)：(0.7~1.2)：(0.5~0.9)：(1.8~2.8)：(0.2~0.4)：(1.7~2.2)：(0.2~0.6)：(0.03~0.04)：(0.07~0.08)：(0.05~0.06)：(0.26~0.28)。 In the above traditional Chinese medicine composition, the Salvia miltiorrhiza extract preferably contains (parts by weight): Danshensu: Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Dan Phenolic acid A: notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginsenoside Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = (3~4): (0.9~1.2) :(1.4~2.0):(0.5~0.7):(0.5~0.9):(1~1.6):(0.7~1.2):(0.5~0.9):(1.8~2.8):(0.2~0.4):( 1.7~2.2): (0.2~0.6): (0.03~0.04): (0.07~0.08): (0.05~0.06): (0.26~0.28).

在上述中藥組合物中，所述丹參三七提取物更優選含有(重量份)：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參 皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=3.6：1.1：1.7：0.6：0.7：1.3：0.9：0.7：2.4：0.3：1.8：0.4：0.03：0.07：0.06：0.27。 In the above traditional Chinese medicine composition, the Salvia miltiorrhiza extract preferably contains (parts by weight): Danshensu: Salvianolic acid T: Protocatechuic aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginseng Saponin Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA=3.6:1.1:1.7:0.6:0.7:1.3:0.9:0.7:2.4:0.3:1.8:0.4:0.03:0.07:0.06 :0.27.

上述中藥組合物可以通過對丹參和三七進行提取加工得到提取物，再加入冰片進行混合而製備得到。 The above traditional Chinese medicine composition can be prepared by extracting and processing Danshen and Sanqi, and adding the borneol to mix.

本發明的中藥組合物優選通過下述方法製備：(1)丹參、三七藥材在鹼性條件下，用水煎煮，煎煮液過濾，濾液濃縮醇沉，取上清液濾過，回收乙醇得浸膏(或進一步將浸膏乾燥)，即為丹參三七提取物；(2)向丹參三七提取物中加入冰片，進行混勻，其中，丹參和三七可以在相同鹼性條件下的水中分別進行煎煮；或在同一鹼性條件下的水中煎煮。 The traditional Chinese medicine composition of the present invention is preferably prepared by the following method: (1) Salvia miltiorrhiza and Radix Notoginseng medicinal materials are decocted with water under alkaline conditions, filtered by boiling liquid, and the filtrate is concentrated and alcohol-precipitated, and the supernatant is filtered to recover ethanol. The extract (or further dry the extract) is the extract of Salvia miltiorrhiza Bge.; (2) adding borneol to the extract of Salvia miltiorrhiza Bunge. The mixture is mixed, wherein Danshen and Sanqi can be under the same alkaline conditions. Decoction in water; or decoction in water under the same alkaline conditions.

優選地，所述丹參三七提取物可以通過下述方法製備：步驟(1)：將丹參三七在鹼性下水溶液中煎煮1~3次，每次1~3小時，過濾，得濾液I；步驟(2)：將藥渣加水煎煮1~3次，每次1~3小時，濾過，濾液II；步驟(3)：將濾液I、II合併濃縮，濃縮液醇沉，靜置，取上清液，過濾，回收乙醇，濃縮得浸膏，或將浸膏乾燥，即得丹參三七提取物。 Preferably, the extract of Salvia miltiorrhiza can be prepared by the following method: Step (1): Decoction of Salvia miltiorrhiza Bge. in an alkaline aqueous solution for 1 to 3 times, each time for 1 to 3 hours, and filtering to obtain a filtrate. I; Step (2): decoct the dregs with water for 1~3 times, each time for 1-3 hours, filter, filtrate II; Step (3): Concentrate the filtrates I and II, concentrate the alcohol, and let stand Take the supernatant, filter, recover the ethanol, concentrate to obtain the extract, or dry the extract to obtain the extract of Salvia miltiorrhiza.

其中，步驟(1)中的鹼性水溶液包括，但不限於碳酸氫鈉、碳酸鈉、磷酸氫鈉、磷酸二氫鈉、氫氧化鈉、氫氧化鉀、氫氧化鎂水溶液中的一種或幾種，pH為7.5~9.0，上述鹼性水溶液中的堿的加入量為藥材量的1~4.5重量%、優選2.25~3重量%，以保證丹參素鈉和丹酚酸T提取完全。 Wherein, the alkaline aqueous solution in the step (1) includes, but is not limited to, one or more of sodium hydrogencarbonate, sodium carbonate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, potassium hydroxide, and magnesium hydroxide aqueous solution. The pH is 7.5 to 9.0, and the amount of strontium added in the above alkaline aqueous solution is 1 to 4.5% by weight, preferably 2.25 to 3% by weight, based on the amount of the medicinal material, so as to ensure complete extraction of sodium danshensu and salvianolic acid T.

步驟(3)中優選加入50%~100%的乙醇、優選95%的乙醇進行醇沉，優選醇沉至乙醇的濃度為60%~75%。 Preferably, in step (3), 50% to 100% ethanol, preferably 95% ethanol is added for alcohol precipitation, preferably the concentration of alcohol to ethanol is 60% to 75%.

更優選地，本發明的丹參三七提取物通過下述方法製備： 步驟(1)將丹參藥材切成5cm以下、優選1-2cm的段，將三七藥材粉碎成1cm的顆粒，稱取占總藥材量2.25~3重量%的碳酸氫鈉，將稱量好的丹參、三七、碳酸氫鈉投入提取罐中，每罐加5倍量工藝用水，加熱煮沸，保持沸騰2h±20min，過濾，步驟(2)將藥渣進行第二次提取，加入4倍量水，加熱煮沸，保持沸騰1h±15min，過濾，藥渣棄去；步驟(3)提取液減壓濃縮至相對密度為1.16~1.20(80±5℃)或相應48%~52%的糖度，得濃縮液，將濃縮液打入醇沉罐中，加入適量乙醇調至含醇量為65%~70%，靜置12~24小時，至沉澱完全，分離上清液，棄去沉澱，將上清液濃縮得浸膏，或將浸膏乾燥，即得丹參三七提取物。 More preferably, the Salvia miltiorrhiza extract of the present invention is prepared by the following method: Step (1) cutting the Salvia miltiorrhiza medicinal material into segments of 5 cm or less, preferably 1-2 cm, pulverizing the medicinal materials of Panax notoginseng into 1 cm granules, and weighing the sodium bicarbonate in an amount of 2.25 to 3% by weight of the total medicinal material, which will be weighed well. Danshen, Sanqi, sodium bicarbonate are put into the extraction tank, adding 5 times of process water per tank, heating and boiling, keeping boiling for 2h±20min, filtering, step (2) to extract the dregs for the second time, adding 4 times Water, heat and boil, keep boiling for 1h ± 15min, filter, discard the drug residue; step (3) extract concentrated under reduced pressure to a relative density of 1.16 ~ 1.20 (80 ± 5 ° C) or corresponding 48% ~ 52% sugar, The concentrated liquid is obtained, and the concentrated liquid is put into the alcohol precipitation tank, and the appropriate amount of ethanol is added to adjust the alcohol content to 65% to 70%, and the mixture is allowed to stand for 12 to 24 hours until the precipitation is complete, the supernatant is separated, and the precipitate is discarded. The supernatant is concentrated to obtain an extract, or the extract is dried to obtain a salvia miltiorrhiza extract.

其中，步驟(1)中的5倍量是指藥材總重量的5倍量，同樣地，步驟(2)中的4倍量是指藥渣總重量的4倍量。 Here, the 5-fold amount in the step (1) means 5 times the total weight of the medicinal material, and similarly, the 4-fold amount in the step (2) means 4 times the total weight of the medicinal slag.

本發明中的中藥組合物是由原藥材按重量份丹參75~90份、三七10~25份和冰片0.1~4份製成的。 The traditional Chinese medicine composition of the present invention is prepared from the original medicine according to the weight of 75-90 parts of Danshen, 10~25 parts of Sanqi and 0.1~4 parts of borneol.

優選的中藥組合物由原藥材按重量份丹參80~86份、三七15~18份和冰片0.2~2份製成。 The preferred traditional Chinese medicine composition is prepared from the original medicinal materials by weight of 80-86 parts of Salvia miltiorrhiza, 15-18 parts of Sanqi and 0.2~2 parts of borneol.

最優選的中藥組合物由原藥材按重量份丹參82~84份、三七16~17份和冰片0.4~1.2份製成。 The most preferred traditional Chinese medicine composition is prepared from 82 to 84 parts by weight of Danshen, 16 to 17 parts of Sanqi and 0.4 to 1.2 parts of borneol.

本發明的中藥組合物可以是浸膏也可以是粉末。 The traditional Chinese medicine composition of the present invention may be an extract or a powder.

在對上述丹參三七提取物的有效成分進行檢測的過程中，首次發現其含有上述重量比例的有效組分，並首次從中分離得到新的化合物丹酚酸T。 In the process of detecting the active ingredient of the above-mentioned extract of Salvia miltiorrhiza Bge., it was found for the first time that it contained the above-mentioned effective component of the weight ratio, and the new compound salvianolic acid T was isolated for the first time.

本發明所述的丹酚酸T是酚酸類新化合物，經過化合物的理化性質、高分辨質譜(QFT-ESI)、電噴霧質譜(ESI-MS)、1H-NMR、13C-NMR、DEPT、COSY、HMBC、HMQC、CD等圖譜的鑒定(圖1-圖10)，確證了其結構。 The salvianolic acid T of the present invention is a novel phenolic acid compound, and has undergone physical and chemical properties, high resolution mass spectrometry (QFT-ESI), electrospray ionization mass spectrometry (ESI-MS), 1 H-NMR, 13 C-NMR, DEPT. The identification of maps such as COSY, HMBC, HMQC, and CD (Fig. 1 - Fig. 10) confirmed the structure.

其結構式如下： Its structural formula is as follows:

結構式(I) Structural formula (I)

1H-NMR(氫譜)提示分子中有1個連氧次甲基質子信號δ 4.93(1H，dd，8.0，4.5Hz)；11個芳香質子信號δ 6.85(1H，d，8.5Hz)、δ 7.31(1H，d，8.5Hz)、δ 7.41(1H，d，15.5Hz)、δ 6.27(1H，d，15.5Hz)、δ 6.62(1H，s)、δ 6.63(1H，d，8.0Hz)、δ 6.47(1H，d，8.0Hz)、δ 6.44(1H，d，2.0Hz)、δ 6.55(1H，d，8.5Hz)、δ 6.43(1H，dd，8.5，2.0Hz)、δ 7.69(1H，s)；2個脂肪族質子信號δ 2.89(2H，ddd，14.0，8.0，4.5Hz)。 1 H-NMR (hydrogen spectrum) indicates that there is one oxymethylene proton signal δ 4.93 (1H, dd, 8.0, 4.5 Hz) in the molecule; 11 aromatic proton signals δ 6.85 (1H, d, 8.5 Hz), δ 7.31 (1H, d, 8.5 Hz), δ 7.41 (1H, d, 15.5 Hz), δ 6.27 (1H, d, 15.5 Hz), δ 6.62 (1H, s), δ 6.63 (1H, d, 8.0 Hz) ), δ 6.47 (1H, d, 8.0 Hz), δ 6.44 (1H, d, 2.0 Hz), δ 6.55 (1H, d, 8.5 Hz), δ 6.43 (1H, dd, 8.5, 2.0 Hz), δ 7.69 (1H, s); 2 aliphatic proton signals δ 2.89 (2H, ddd, 14.0, 8.0, 4.5 Hz).

13C-NMR(碳譜)給出27個碳信號，其中1個脂肪碳信號δ 36.0；1個連氧次甲基碳信號δ 72.8；3個羰基碳信號δ 166.0、δ 170.6、δ 168.4；22個雙鍵碳信號δ 123.7、δ 126.4、δ 142.9、δ 147.7、δ 115.0、δ 118.4、δ 143.7、δ 113.9、δ 127.1、δ 116.5、δ 143.9、δ 144.8、δ 115.5、δ 120.0、δ 126.0、δ 117.3、δ 144.8、δ 147.2、δ 115.3、δ 122.9、δ 141.1、δ 123.4。 13 C-NMR (carbon spectrum) gives 27 carbon signals, one of which has a fat carbon signal of δ 36.0; one oxymethylidene carbon signal of δ 72.8; three carbonyl carbon signals of δ 166.0, δ 170.6, δ 168.4; 22 double bond carbon signals δ 123.7, δ 126.4, δ 142.9, δ 147.7, δ 115.0, δ 118.4, δ 143.7, δ 113.9, δ 127.1, δ 116.5, δ 143.9, δ 144.8, δ 115.5, δ 120.0, δ 126.0 , δ 117.3, δ 144.8, δ 147.2, δ 115.3, δ 122.9, δ 141.1, δ 123.4.

本發明化合物兩種異構體的旋光分別為：-157.5°、196.6°。對C-8′絕對構型設定為S/R構型的化合物分別進行了分子結構優化，然後採用具有TD-SCF的BPV86方法，在6-31++G(2d，p)基組下進行計算，讀取其計算結果與本發明化合物CD譜對照，最終結果發現兩種構型化合物的計算結果與本發明化合物的實驗CD譜圖基本重合，推斷本發明化合物兩種異構體的C-8′的絕對構型分別為S構型和R構型(參見圖10)。本發明的化合物主要 HMBC相關如下： The optical isomers of the two isomers of the present invention are: -157.5° and 196.6°, respectively. The molecular structure optimization was carried out for the compounds with the C-8' absolute configuration set to the S/R configuration, and then the BPV86 method with TD-SCF was used in the 6-31++G (2d, p) basis group. Calculation, reading the calculation results and comparing with the CD spectrum of the compound of the present invention, and finally found that the calculation results of the two configuration compounds substantially coincide with the experimental CD spectrum of the compound of the present invention, and it is inferred that the two isomers of the present invention are C- The absolute configuration of 8' is the S configuration and the R configuration, respectively (see Figure 10). The main HMBCs of the compounds of the invention are as follows:

丹酚酸T可以由下述方法製備得到：1、提取：將丹參藥材或丹參藥材與其他藥材的混合物進行水提，濾液濃縮為水提浸膏，然後醇沉，使上清液濃縮為醇沉浸膏；2、分離：將步驟1中所得醇沉浸膏經水稀釋後，過大孔吸附樹脂，用酸性水溶液沖洗除去雜質，然後用乙醇洗脫，將乙醇洗脫液濃縮為浸膏；3、純化：將步驟2所得浸膏使用高壓製備液相色譜儀進行純化，色譜填料為C18反相矽膠柱，洗脫液為乙腈-水-甲酸，等度洗脫或梯度洗脫，檢測波長280nm；用高效液相色譜監測洗脫過程，收集含有丹酚酸T的洗脫液，濃縮後得所述丹酚酸T。 Salvianolic acid T can be prepared by the following method: 1. Extraction: water is extracted from the mixture of Salvia miltiorrhiza or Salvia miltiorrhiza and other herbs, and the filtrate is concentrated into water extract extract, then alcohol precipitation, and the supernatant is concentrated to alcohol. Immersion paste; 2, separation: after the alcoholic extract obtained in step 1 is diluted with water, the resin is adsorbed through the macropores, and the impurities are washed away with an acidic aqueous solution, and then eluted with ethanol to concentrate the ethanol eluate into an extract; Purification: The extract obtained in the step 2 is purified by using a high-pressure preparative liquid chromatograph. The chromatographic packing is a C18 reverse phase gel column, and the eluent is acetonitrile-water-formic acid, isocratic or gradient elution, and the detection wavelength is 280 nm; The elution process was monitored by high performance liquid chromatography, and the eluate containing salvianolic acid T was collected and concentrated to obtain the salvianolic acid T.

在一個實施方式中，本發明提供了所述中藥組合物的藥物製劑，所述藥物製劑包含本發明的中藥組合物和一種或多種藥學上可接受的載體。本發明的中藥組合物在其製劑中所占重量百分比可以為0.1%~99.9%，其餘為藥學上可接受的載體。 In one embodiment, the invention provides a pharmaceutical formulation of the traditional Chinese medicine composition comprising a traditional Chinese medicine composition of the invention and one or more pharmaceutically acceptable carriers. The traditional Chinese medicine composition of the present invention may comprise from 0.1% to 99.9% by weight of the preparation, and the balance being a pharmaceutically acceptable carrier.

本發明所述的藥物製劑為單位劑量藥物製劑形式，所述單位劑量是指製劑的單位，如片劑的每片、膠囊的每粒膠囊、口服液的每瓶、顆粒劑的每袋等，並且可以通過用藥學領域熟知的任一種方法製備。所有方法包括使本發明的中藥組合物與載體結合的步驟，該載體構成一種或多種輔助成分。一般來說，該製劑的製備過程如下：使本發明的中藥組合物與液體載體、或微細粉碎的固體載體、或二者的結合均勻而緊密的結合，然後，如果必要的 話，使產物成型為所必須的製劑。通常可使用標準的製藥技術，即可將本發明的中藥組合物、和藥用載體製得本發明的藥物製劑，這些方法包括混合、製粒和壓制。本領域技術人員所熟知的是，可藥用載體或稀釋劑的形式和特性取決於與其混合的活性成分的量、給藥途徑和其他已知因素。 The pharmaceutical preparation of the present invention is in the form of a unit dosage pharmaceutical preparation, and the unit dosage refers to a unit of the preparation, such as each tablet of the tablet, each capsule of the capsule, each bottle of the oral liquid, and each bag of the granule, etc. And it can be prepared by any method well known in the pharmaceutical art. All methods include the step of bringing into association a traditional Chinese medicine composition of the present invention with a carrier which constitutes one or more accessory ingredients. In general, the preparation process of the preparation is as follows: the combination of the traditional Chinese medicine composition of the present invention with a liquid carrier, or a finely pulverized solid carrier, or a combination thereof, is uniformly and tightly combined, and then, if necessary In this case, the product is shaped into the necessary preparation. The pharmaceutical preparations of the present invention can be prepared by standard pharmaceutical techniques, i.e., the traditional Chinese medicine compositions of the present invention, and pharmaceutical carriers, including mixing, granulating, and compressing. It is well known to those skilled in the art that the form and nature of the pharmaceutically acceptable carrier or diluent will depend on the amount of active ingredient(s), the route of administration, and other known factors.

其藥物製劑形式可以是任何可藥用的劑型，這些劑型包括：片劑、糖衣片劑、薄膜衣片劑、腸溶衣片劑、膠囊劑、硬膠囊劑、軟膠囊劑、口服液、***劑、顆粒劑、沖劑、丸劑、散劑、膏劑、丹劑、混懸劑、粉劑、溶液劑、注射劑、栓劑、軟膏劑、硬膏劑、霜劑、噴霧劑、滴劑、貼劑。本發明的製劑，優選的是口服劑型，如：膠囊劑、片劑、口服液、顆粒劑、丸劑、散劑、丹劑、膏劑等。 The pharmaceutical preparation form may be any pharmaceutically acceptable dosage form, and the dosage forms include: tablets, sugar-coated tablets, film-coated tablets, enteric coated tablets, capsules, hard capsules, soft capsules, oral liquids, mouths. Containing agents, granules, granules, pills, powders, ointments, dans, suspensions, powders, solutions, injections, suppositories, ointments, plasters, creams, sprays, drops, patches. The preparation of the present invention is preferably an oral dosage form such as a capsule, a tablet, an oral solution, a granule, a pill, a powder, an agent, a paste or the like.

其口服給藥的製劑可含有常用的賦形劑，諸如黏合劑、填充劑、稀釋劑、壓片劑、潤滑劑、崩解劑、著色劑、調味劑和濕潤劑，必要時可對片劑進行包衣。 The preparation for oral administration may contain conventional excipients such as a binder, a filler, a diluent, a tablet, a lubricant, a disintegrant, a coloring agent, a flavoring agent, and a wetting agent, and if necessary, a tablet Carry out the coating.

適用的填充劑包括纖維素、甘露糖醇、乳糖和其他類似的填充劑。適宜的崩解劑包括澱粉、聚乙烯吡咯烷酮和澱粉衍生物，例如羥基乙酸澱粉鈉。適宜的潤滑劑包括，例如硬脂酸鎂。適宜的藥物可接受的濕潤劑包括十二烷基硫酸鈉。 Suitable fillers include cellulose, mannitol, lactose and other similar fillers. Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulfate.

可通過混合、填充、壓片等常用的方法製備固體口服組合物。進行反復混合可使活性物質分佈在整個使用大量填充劑的那些組合物中。 Solid oral compositions can be prepared by conventional methods such as mixing, filling, tableting, and the like. Repeated mixing allows the active material to be distributed throughout those compositions that use large amounts of filler.

口服液體製劑的形式例如可以是水性或油性懸浮液、溶液、乳劑、糖漿劑或酏劑，或者可以是一種在使用前可用水或其他適宜的載體複配的乾燥產品。這種液體製劑可含有常規的添加劑，諸如懸浮劑，例如山梨醇、糖漿、甲基纖維素、明膠、羥乙基纖維素、羧甲基纖維素、硬脂酸鋁凝膠或氫化食用脂肪，乳化劑，例如卵磷脂、脫水山梨醇一油酸酯或***膠；非水性載體(它 們可以包括食用油)，例如杏仁油、分餾椰子油、諸如甘油的酯的油性酯、丙二醇或乙醇；防腐劑，例如對羥基苯甲酯或對羥基苯甲酸丙酯或山梨酸，並且如果需要，可含有常規的香味劑或著色劑。 The oral liquid preparation may be in the form of, for example, an aqueous or oily suspension, solution, emulsion, syrup or elixir, or may be a dry product which may be formulated with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents such as sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats. An emulsifier such as lecithin, sorbitan monooleate or gum arabic; a non-aqueous carrier (it They may include edible oils) such as almond oil, fractionated coconut oil, oily esters of esters such as glycerol, propylene glycol or ethanol; preservatives such as p-hydroxybenzyl or propylparaben or sorbic acid, and if needed It may contain conventional flavoring agents or colorants.

對於注射劑，製備的液體單位劑型含有本發明的活性物質和無菌載體。根據載體和濃度，可以將此化合物懸浮或者溶解。溶液的製備通常是通過將活性物質溶解在一種載體中，在將其裝入一種適宜的小瓶或安瓿前過濾消毒，然後密封。輔料例如一種局部麻醉劑、防腐劑和緩沖劑也可以溶解在這種載體中。為了提高其穩定性，可在裝入小瓶以後將這種組合物冰凍，並在真空下將水除去。 For injection, the liquid unit dosage form prepared contains the active substance of the invention and a sterile vehicle. This compound can be suspended or dissolved depending on the carrier and concentration. The solution is usually prepared by dissolving the active substance in a carrier, sterilizing it by filtration before filling it into a suitable vial or ampoule, and then sealing. Excipients such as a local anesthetic, preservative and buffer may also be dissolved in such a carrier. To increase its stability, the composition can be frozen after filling the vial and the water removed under vacuum.

在製備成藥劑時可選擇性的加入適合的藥學上可接受的載體，所述藥學上可接受的載體選自：甘露醇、山梨醇、焦亞硫酸鈉、亞硫酸氫鈉、硫代硫酸鈉、鹽酸半胱氨酸、巰基乙酸、蛋氨酸、維生素C、EDTA二鈉、EDTA鈣鈉，一價鹼金屬的碳酸鹽、醋酸鹽、磷酸鹽或其水溶液、鹽酸、醋酸、硫酸、磷酸、氨基酸、氯化鈉、氯化鉀、乳酸鈉、木糖醇、麥芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、澱粉、蔗糖、乳糖、甘露糖醇、矽衍生物、纖維素及其衍生物、藻酸鹽、明膠、聚乙烯吡咯烷酮、甘油、土溫80、瓊脂、碳酸鈣、碳酸氫鈣、表面活性劑、聚乙二醇、環糊精、β-環糊精、磷脂類材料、高嶺土、滑石粉、硬脂酸鈣、硬脂酸鎂等。 A suitable pharmaceutically acceptable carrier may be optionally added in the preparation of the medicament, the pharmaceutically acceptable carrier being selected from the group consisting of: mannitol, sorbitol, sodium metabisulfite, sodium hydrogen sulfite, sodium thiosulfate, hydrochloric acid. Cysteine, thioglycolic acid, methionine, vitamin C, disodium EDTA, calcium EDTA, monovalent alkali metal carbonate, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulfuric acid, phosphoric acid, amino acid, chlorination Sodium, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, anthraquinone derivatives, cellulose and its derivatives, alginate, gelatin , polyvinylpyrrolidone, glycerin, soil temperature 80, agar, calcium carbonate, calcium hydrogencarbonate, surfactant, polyethylene glycol, cyclodextrin, β-cyclodextrin, phospholipid materials, kaolin, talcum powder, stearic acid Calcium acid, magnesium stearate, and the like.

本發明優選將中藥組合物製成滴丸製劑，更優選微滴丸製劑。 In the present invention, the traditional Chinese medicine composition is preferably made into a dropping pill preparation, more preferably a micro-dropping preparation.

在另一個實施方式中，本發明提供一種複方丹參微滴丸，所述的複方丹參微滴丸是由重量比為1：5~5：1的中藥組合物與滴丸基質製成；優選地，本發明的複方丹參微滴丸是由重量比為1：3~3：1的中藥組合物與滴丸基質製成；最優選地，本發明的複方丹參微滴丸是由重量比為1：(1~3)的中藥組合物與滴丸基質組成。 In another embodiment, the present invention provides a compound Danshen microdroplet pellet, wherein the compound Danshen microdroplet pellet is made of a traditional Chinese medicine composition and a dropping pellet matrix in a weight ratio of 1:5 to 5:1; preferably The compound Danshen microdroplet of the present invention is prepared from a traditional Chinese medicine composition and a dropping matrix of a weight ratio of 1:3 to 3:1; most preferably, the compound Danshen microdropping pellet of the present invention is composed of a weight ratio of 1 The composition of the traditional Chinese medicine of (1~3) is composed of the matrix of the dropping pills.

本發明的複方丹參微滴丸的製備方法包括如下步驟：(1)化料步驟：將藥物與滴丸基質投入均質機中，以1000~5000rpm均質混合，時間1~200min，然後，以300.0~10000rpm均質化料，時間1~100min，在化料過程中，溫度保持在60~100℃，得熔融藥液，所述藥物與所述滴丸基質的重量比為1：5~5：1；(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度70~300℃、滴製振動頻率2~2000Hz、滴製壓力0.5~4.0Bar、加速度1-20G的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配；(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm~4.0mm固態滴丸，所述冷卻氣體的溫度為0℃以下。 The preparation method of the compound Danshen micro-drop pellet of the invention comprises the following steps: (1) chemical step: the medicine and the dropping matrix are put into a homogenizer, and the mixture is homogeneously mixed at 1000-5000 rpm for 1 to 200 minutes, and then, 300.0~. 10000 rpm homogenization material, time 1~100min, during the chemical process, the temperature is maintained at 60~100 ° C, the molten liquid is obtained, the weight ratio of the drug to the dropping matrix is 1:5~5:1; (2) Drip step: the above molten liquid is transported to the dripper, under the conditions of a dripper temperature of 70-300 ° C, a dropping vibration frequency of 2 to 2000 Hz, a dropping pressure of 0.5 to 4.0 Bar, and an acceleration of 1-20 G, After the drip vibrating drop, the dropping speed is matched with the step (1) the material speed; (3) the condensation step: the dripping drug droplet is rapidly cooled in the cooling gas, and solidified into a solid droplet having a particle diameter of 0.2 mm to 4.0 mm. The pellet has a temperature of the cooling gas of 0 ° C or less.

優選地，本發明的複方丹參微滴丸的製備方法包括如下步驟：(1)化料步驟：將藥物與滴丸基質投入均質機中，以1000~5000rpm均質混合，時間1~200min，然後，以3000~10000rpm均質化料，時間1~100min，在化料過程中，溫度保持在80~100℃，得熔融藥液，所述藥物與所述滴丸基質的重量比為1：3~3：1；(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度70~200℃、滴製振動頻率20~300Hz、滴製壓力0.5~4.0Bar、加速度1-15G的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配；(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm~4.0mm固態滴丸，所述冷卻氣體的溫度為0℃以下。 Preferably, the preparation method of the compound Danshen micro-drop pellet of the present invention comprises the following steps: (1) chemical step: the medicine and the dropping matrix are put into a homogenizer, and the mixture is homogeneously mixed at 1000-5000 rpm for 1 to 200 minutes, and then, The material is homogenized at 3000~10000rpm for 1~100min. During the process of the chemical, the temperature is maintained at 80~100°C, and the molten liquid is obtained. The weight ratio of the drug to the dropping matrix is 1:3~3. (1) Drip step: the above molten liquid is transported to the dripper at a dripper temperature of 70 to 200 ° C, a dropping vibration frequency of 20 to 300 Hz, a dropping pressure of 0.5 to 4.0 Bar, and an acceleration of 1 to 15 G. Under the condition, the drip vibrating drops, the dropping speed is matched with the step (1) the material speed; (3) the condensation step: the dripping medicine drops are rapidly cooled in the cooling gas, and solidified into a particle diameter of 0.2 mm to 4.0. Mm solid drop pellets, the temperature of the cooling gas is below 0 °C.

其中，上述步驟(1)中，所述滴丸基質包括PEG類、山梨醇、木糖醇、乳糖醇、麥芽糖、澱粉、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、***膠、海藻酸、糊精、環糊精、瓊脂、乳糖中的一種或多種組合；優選的滴丸基質為固體PEG，例如PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-5000、PEG-6000、PEG-7000、PEG-8000，進一步優選PEG-1000、 PEG-2000、PEG-3000、PEG-4000、PEG-6000、PEG-8000中的一種或多種組合，最優選為PEG-6000、PEG-4000或PEG-4000和PEG-6000的組合。步驟(1)的均質化可以提高含量均勻性，使含量均勻性由原來的RSD=10%，提高至7%。 Wherein, in the above step (1), the dropping matrix comprises PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose One or more combinations of argin, gum arabic, alginic acid, dextrin, cyclodextrin, agar, lactose; preferred pellet base is solid PEG, such as PEG-1000, PEG-2000, PEG-3000, PEG-4000 PEG-5000, PEG-6000, PEG-7000, PEG-8000, further preferably PEG-1000, One or a combination of PEG-2000, PEG-3000, PEG-4000, PEG-6000, PEG-8000, most preferably PEG-6000, PEG-4000 or a combination of PEG-4000 and PEG-6000. The homogenization of the step (1) can improve the content uniformity, and the content uniformity is improved from the original RSD=10% to 7%.

優選地，上述步驟(1)中，所述藥物與所述滴丸基質的重量比為1：3~3：1，以3000~5000rpm均質混合，時間10~60min，然後，以4000~9000rpm均質化料，時間5~30min，在化料過程中，溫度保持在70~90℃；最優選地，所述藥物與所述滴丸基質的重量比為1：(1~3)，以3000~4000rpm均質混合，時間10-30min，然後，以4000~6000rpm均質化料，時間6~30min，在化料過程中，溫度保持在75~85℃。 Preferably, in the above step (1), the weight ratio of the drug to the dropping matrix is 1:3 to 3:1, and the mixture is homogeneously mixed at 3000 to 5000 rpm for 10 to 60 minutes, and then homogenized at 4000 to 9000 rpm. The chemical material, the time is 5~30min, the temperature is maintained at 70~90 °C during the chemical process; most preferably, the weight ratio of the drug to the dropping matrix is 1: (1~3), 3000~ Homogenize mixing at 4000 rpm for 10-30 min. Then, homogenize the material at 4000~6000 rpm for 6~30 min. During the chemical process, the temperature is maintained at 75-85 °C.

其中，優選地，上述步驟(2)中，滴頭溫度為70~100℃、優選75~85℃；滴製振動頻率為50~300Hz、優選100~200Hz、更優選90~200Hz、更優選130~140Hz、最優選137Hz；加速度3.5~4.5G、優選4.0G；滴製壓力為1.0~3.0Bar、優選1.8Bar；滴製速度為10~40kg/h，優選12~30kg/h，進一步優選15~25kg/h。 Preferably, in the above step (2), the dripper temperature is 70 to 100 ° C, preferably 75 to 85 ° C; the dropping vibration frequency is 50 to 300 Hz, preferably 100 to 200 Hz, more preferably 90 to 200 Hz, and more preferably 130 ~140 Hz, most preferably 137 Hz; acceleration 3.5~4.5G, preferably 4.0G; dropping pressure is 1.0~3.0Bar, preferably 1.8Bar; dropping speed is 10~40kg/h, preferably 12~30kg/h, further preferably 15 ~25kg/h.

上述步驟(3)中，氣體冷卻是指利用低溫冷阱對下落藥滴快速冷卻，使其凝固成形。冷卻氣體的溫度範圍為o℃以下，優選0~-150℃、優選-60℃~-140℃、更優選-80℃~-120℃，優選冷卻氣體為空氣、氮氣、惰性氣體。所得微滴丸的粒徑優選1.0mm~2.0mm。 In the above step (3), the gas cooling means that the falling medicine droplet is rapidly cooled by a low temperature cold trap to be solidified and formed. The temperature of the cooling gas is in the range of o ° C or lower, preferably 0 to -150 ° C, preferably -60 ° C to -140 ° C, more preferably -80 ° C to -120 ° C. Preferably, the cooling gas is air, nitrogen, or an inert gas. The particle diameter of the obtained micropellet is preferably 1.0 mm to 2.0 mm.

進一步地，本發明的微滴丸的製備方法還包括作為步驟(4)的乾燥步驟，優選採用流化乾燥設備乾燥，在-20~100℃、優選-20~90℃乾燥1~4h，得素丸。具體而言，經步驟(3)完成滴製後的低溫滴丸，經過溫度40~150℃、優選溫度40~60℃的流化床乾燥，乾燥時間1~4h、優選1~3h、最優選為2h，得素丸。 Further, the method for preparing the microdroplet of the present invention further comprises the step of drying as the step (4), preferably drying by using a fluidized drying device, and drying at -20 to 100 ° C, preferably -20 to 90 ° C for 1 to 4 hours. Suwan. Specifically, the low-temperature dropping pills after the completion of the dropping in the step (3) are dried in a fluidized bed having a temperature of 40 to 150 ° C and preferably a temperature of 40 to 60 ° C, and the drying time is 1 to 4 hours, preferably 1 to 3 hours, and most preferably. For 2h, get the pill.

上述步驟(4)中，優選如下的梯度升溫乾燥法：於-20~30℃形成流化態，於15~35℃乾燥10~120min，於35~55℃乾燥10~60min，於55~100℃乾燥0~60min；進一步優選如下的梯度升 溫乾燥法：於0~20℃形成流化態，於25℃乾燥60min，於45℃乾燥30min，於55℃乾燥0~30min。該步驟保持滴丸處於流化狀態，解決了滴丸黏連的問題，還提高了效率，產能可達30kg/h。 In the above step (4), the following gradient heating drying method is preferred: a fluidized state is formed at -20 to 30 ° C, dried at 15 to 35 ° C for 10 to 120 minutes, and dried at 35 to 55 ° C for 10 to 60 minutes at 55 to 100. Dry at °C for 0~60min; further preferred is the following gradient Warm drying method: forming a fluidized state at 0 to 20 ° C, drying at 25 ° C for 60 min, drying at 45 ° C for 30 min, and drying at 55 ° C for 0 to 30 min. This step keeps the dropping pills in a fluidized state, solves the problem of sticking of the dropping pills, and improves the efficiency, and the productivity can reach 30 kg/h.

上述步驟(4)中，發明人經過從大量的乾燥方法中進行篩選，結果是，步驟(3)所述素丸採用低濕度環境下晾曬法、包衣鍋乾燥法、真空乾燥箱烘乾法、熱風迴圈乾燥箱烘乾法、履帶式微波乾燥機乾燥法、流化乾燥包衣機乾燥法中一種。從成品率及產能方面考慮，優選包衣鍋乾燥法、履帶式微波乾燥機乾燥法和流化乾燥包衣機乾燥法。從產業化的角度考慮，優選流化床乾燥法，更優選流化乾燥包衣機乾燥法。表1示出了不同乾燥方法的優劣。 In the above step (4), the inventors have screened from a large number of drying methods, and as a result, the pill in the step (3) is subjected to a drying method in a low-humidity environment, a coating pan drying method, and a vacuum drying oven drying method. The hot air loop drying oven drying method, the crawler type microwave dryer drying method, and the fluidized drying coating machine drying method. From the viewpoint of yield and productivity, a coating pan drying method, a crawler type microwave dryer drying method, and a fluidized drying coater drying method are preferred. From the viewpoint of industrialization, a fluidized bed drying method is preferred, and a fluidized drying coater drying method is more preferred. Table 1 shows the pros and cons of different drying methods.

進一步地，本發明的微滴丸的製備方法還包括作為步驟(5)的包衣步驟。該步驟是在所述步驟(4)得到的素丸處於流化狀態下，在30~65℃溫度下對所述素丸進行包衣；包衣液濃度為5~25wt%、優選18~20wt%，其中，包衣材料選自：蟲膠、苯二甲酸醋酸纖維素、丙烯酸甲酯、甲基丙烯酸甲酯或歐巴代。所述包衣材料與素丸的重量比為1：50~1：10、優選1：50~1：25。 Further, the method for preparing a microdroplet of the present invention further comprises as a coating step of the step (5). In this step, the pellets obtained in the step (4) are in a fluidized state, and the pellets are coated at a temperature of 30 to 65 ° C; the concentration of the coating liquid is 5 to 25 wt%, preferably 18 to 20 wt. %, wherein the coating material is selected from the group consisting of: shellac, cellulose acetate phthalate, methyl acrylate, methyl methacrylate or Opadry. The weight ratio of the coating material to the pill is from 1:50 to 1:10, preferably from 1:50 to 1:25.

為了更好地實施本發明的微滴丸的製備方法，優選在步驟(1)前，還可以具有物料預混步驟，將藥物浸膏或粉末加水後，於30~80℃攪拌10min以上，得到藥物預混料，以保證水分均一。該步驟可以彌補乾粉投料的缺點。 In order to better carry out the preparation method of the micro-droplet of the present invention, it is preferred to have a material pre-mixing step before the step (1), and after adding the drug to the drug extract or powder, stirring at 30-80 ° C for more than 10 minutes, Premix the drug to ensure a uniform moisture. This step can make up for the shortcomings of dry powder feeding.

由本發明的方法製得的滴丸可以直接包裝，也可以裝入膠囊殼後製成膠囊劑。在製成膠囊劑後，還可增加逐粒膠囊稱重的步驟，灌裝後的膠囊在包裝之前進行高速逐粒稱重，以剔除可能存在的不合格膠囊。 The dropping pills obtained by the method of the present invention may be directly packaged or may be enclosed in a capsule shell to form a capsule. After the capsule is made, the step of weighing the capsules can be increased, and the capsules after filling are weighed at a high speed and granulated before packaging to eliminate the defective capsules that may exist.

本發明的上述方法的特點在於：首次將振動滴製、氣體冷卻與流化乾燥包衣處理的工藝創造性地結合在一起，並應用於滴丸製劑和滴丸膠囊製劑，由此提升了滴丸的生產速率和成形品質，更簡化了藥品生產工序，本發明的方法的具體優點如下： The above method of the present invention is characterized in that the process of vibration dripping, gas cooling and fluidized drying coating treatment is creatively combined for the first time, and is applied to a dropping pill preparation and a dropping pill capsule preparation, thereby improving the dropping pill The production rate and forming quality further simplify the pharmaceutical production process, and the specific advantages of the method of the present invention are as follows:

1.將傳統滴丸製備(自然滴製/壓力滴製+冷卻液冷卻)改變為振動滴製+氣體冷卻。氣體冷卻的工藝滿足了滴丸製備中對高速 滴製、製備滴丸能力(粒徑2.5mm以下)以及提高載藥量的要求，成倍地提高滴丸的載藥量，大幅降低了滴丸基質的用量和服用劑量。另外，從產能方面考慮，從傳統滴製的1~2丸/秒提升到1000~1250丸/秒，極大地提高了產能；滴製丸徑的範圍從2mm~4mm擴大到0.2mm~4mm的滴丸，可生產出能更好地滿足膠囊灌裝要求的微滴丸；通過調節振動參數和流化載藥包衣，可將傳統滴丸的載藥量從25wt%左右提高至50wt%以上，滴丸基質的用量也大幅減少。 1. Change the traditional dropping pill preparation (natural dripping / pressure drip + coolant cooling) to vibrating drip + gas cooling. The gas cooling process satisfies the high speed in the preparation of the dropping pills The ability to drip, prepare the dropping pills (particle size below 2.5 mm) and increase the drug loading amount doubles the drug loading of the dropping pills, and greatly reduces the dosage and dosage of the dropping pills. In addition, from the aspect of productivity, it has increased the production capacity from 1~2 pills/sec of traditional dripping to 1000~1250 pill/sec, greatly increasing the productivity; the range of the dropping diameter is from 2mm~4mm to 0.2mm~4mm. Dropping pills can produce micro-dropping pills that can better meet the requirements of capsule filling; by adjusting the vibration parameters and fluidized drug-loading coating, the drug loading of traditional dropping pills can be increased from about 25wt% to more than 50wt%. The dosage of the dropping pill matrix is also greatly reduced.

2.由於採用低溫空氣、氮氣或惰性氣體進行冷卻，避免了傳統的採用液體石蠟、矽油等液體冷凝方式的後續殘留溶劑處理工序(如後續脫油處理步驟)，因而簡化了操作工序，完全無有機溶劑殘留，並降低了滴丸製備的成本。 2. Due to the use of low temperature air, nitrogen or inert gas for cooling, the conventional residual solvent treatment process (such as the subsequent deoiling treatment step) using liquid condensation methods such as liquid paraffin and eucalyptus oil is avoided, thereby simplifying the operation process and completely eliminating The organic solvent remains and reduces the cost of pellet preparation.

3.增加流化乾燥包衣工藝，不僅解決了空氣冷卻方法製備滴丸在存放過程中可能出現的黏連及成分析出、揮發油成分降低等問題，還能夠縮短乾燥時間(從4~24h縮短到僅需2h)。使用流化包衣技術，噴射熔融藥液進行載藥包衣，可進一步提高滴丸的載藥量。也可使用該工序噴射進行滴丸包衣，以滿足不同工藝要求(如緩釋包衣、薄膜包衣、糖包衣等)。由於流化處理方式較溫和，不僅可確保滴丸水分達到穩定值，也提高了載藥及包衣的均勻性，不會出現傳統滴丸發生裂丸和出現白點的現象，同時提高了產品收率。 3. Increasing the fluidized and dry coating process not only solves the problems of adhesion and analysis of the dropping pills in the storage process, but also reduces the volatile oil composition, and shortens the drying time (from 4 to 24 hours). It only takes 2 hours). The use of a fluidized coating technique to spray a molten chemical solution for drug loading can further increase the drug loading of the dropping pills. This process can also be used to spray the pills to meet different process requirements (such as sustained release coating, film coating, sugar coating, etc.). Due to the milder fluidization treatment method, not only can the water content of the dropping pills reach a stable value, but also the uniformity of drug loading and coating can be improved, and the phenomenon that the traditional dropping pills are cracked and white spots appear, and the product collection is improved. rate.

本發明的微滴丸(以由實施例15所製備的複方丹參微滴丸為例)與現有的微滴丸在理化參數方面的比較匯總與下表2中。 A comparison of the physical and chemical parameters of the microdroplets of the present invention (for example, the compound Danshen microdroplets prepared in Example 15) and the existing microdroplets is summarized in Table 2 below.

實施例 Example

以下通過實施例對本發明的工藝進一步加以詳細說明。該實施例僅用於說明本發明，而沒有意圖對本發明構成限制。 The process of the present invention will be further described in detail below by way of examples. This example is for illustrative purposes only and is not intended to limit the invention.

丹參三七提取物各組分的含量測定方法 Method for determining the content of each component of Salvia miltiorrhiza extract

在以下實施例中，各中藥組合物的各組分：丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、二氫丹參酮I、丹參酮I、隱丹參酮、丹參酮IIA、三七皂苷R1、人參皂苷Rg1、人參皂苷Re、人參皂苷Rb1、人參皂苷Rd的含量按照下述方法進行測定。 In the following examples, each component of each traditional Chinese medicine composition: Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, dihydrogen The contents of tanshinone I, tanshinone I, cryptotanshinone, tanshinone IIA, notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd were measured by the following methods.

酚酸類和丹參酮類組分的檢測：對照品及供試品溶液的配製 Determination of phenolic acids and tanshinones: preparation of reference substance and test solution

對照品溶液：精密稱取一定量對照品丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、二氫丹參酮I、丹參酮I、隱丹參酮、丹參酮IIA置於10ml量瓶中，用甲醇溶解後稀釋至刻度，根據需要進行稀釋、搖勻，分別製成以下濃度的溶液：丹參素0.0315mg/ml、丹酚酸T 0.04596mg/ml、原兒茶醛0.07556mg/ml、丹酚酸D 0.04385mg/ml、迷迭香酸0.04263mg/ml、 丹酚酸B 0.04248mg/ml、丹酚酸A 0.1118mg/ml、二氫丹參酮I 0.02098mg/ml、丹參酮I 0.02085mg/ml、隱丹參酮0.02442mg/ml、丹參酮IIA 0.01992mg/ml，經0.22μm膜過濾，即得對照品溶液。 Reference solution: accurately weigh a certain amount of reference substance Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, dihydrotanshinone I, tanshinone I, cryptotanshinone, tanshinone IIA in a 10ml volumetric flask, dissolved in methanol and diluted to the mark, diluted and shaken as needed, respectively, to make the following concentrations of solution: Danshensu 0.0315mg / ml, salvianolic acid T 0.04596 Mg/ml, protocatechuic aldehyde 0.07556mg/ml, salvianolic acid D 0.04385mg/ml, rosmarinic acid 0.04263mg/ml, Salvianolic acid B 0.04248mg/ml, salvianolic acid A 0.1118mg/ml, dihydrotanshinone I 0.02098mg/ml, tanshinone I 0.02085mg/ml, cryptotanshinone 0.02442mg/ml, tanshinone IIA 0.01992mg/ml, 0.22 The μm membrane is filtered to obtain a reference solution.

供試品溶液：精密稱取0.1g丹參三七提取物樣品放置於10ml量瓶中，用純水溶解後，稀釋至刻度，然後經0.22μm膜過濾，即得供試品溶液。 Test solution: Weigh accurately 0.1 g of Salvia miltiorrhiza extract sample placed in a 10 ml volumetric flask, dissolved in pure water, diluted to the mark, and then filtered through a 0.22 μm membrane to obtain a test solution.

測定方法：分別精密吸取對照品溶液與供試品溶液各10μl，注入超高效液相色譜儀，測定。 Measuring method: 10 μl of each of the reference solution and the test solution were accurately taken up and injected into an ultra-high performance liquid chromatograph for measurement.

色譜柱：Agilent Zorbax SB C18(4.6×250mm，5μm) Column: Agilent Zorbax SB C18 (4.6 x 250 mm, 5 μm)

流速：0.5mL/min Flow rate: 0.5mL/min

柱溫：30℃ Column temperature: 30 ° C

檢測波長：281nm，洗脫條件如下表3： Detection wavelength: 281 nm, elution conditions are shown in Table 3 below:

其中，丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、二氫丹參酮I、丹參酮I、隱丹參酮、丹參酮IIA在281nm波長下的保留時間見圖11和表4。 Among them, Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, dihydrotanshinone I, tanshinone I, cryptotanshinone, tanshinone IIA at 281nm The retention times at wavelengths are shown in Figure 11 and Table 4.

皂苷類組分的檢測：對照品溶液的製備：取三七皂苷R1對照品、人參皂苷Rg1對照品、人參皂苷Rb1對照品、人參皂苷Re、人參皂苷Rd對照品適量，精密稱定，加甲醇製成每1ml分別含0.5mg、2.0mg、1.0mg、0.5mg、0.5mg、0.5mg、1.0mg的溶液，即得。 Determination of saponin components: preparation of reference solution: take the notoginsenoside R1 reference substance, ginsenoside Rg1 reference substance, ginsenoside Rb1 reference substance, ginsenoside Re, ginsenoside Rd reference substance, accurately weighed, add methanol A solution containing 0.5 mg, 2.0 mg, 1.0 mg, 0.5 mg, 0.5 mg, 0.5 mg, and 1.0 mg per 1 ml is obtained.

供試品溶液的製備：精密稱定0.1g樣品，加4%的氨水溶液10ml溶解，通過D101型大孔吸附樹脂柱(內徑為0.7cm，柱高為5cm)，用30ml水洗脫，然後用30ml的30%的甲醇洗脫，再用10ml甲醇洗脫，收集甲醇溶液至10ml量瓶中，搖勻，即得。 Preparation of the test solution: 0.1 g of the sample was accurately weighed, dissolved in 10 ml of a 4% aqueous ammonia solution, and passed through a D101 type macroporous adsorption resin column (inner diameter 0.7 cm, column height 5 cm), and eluted with 30 ml of water. Then, it was eluted with 30 ml of 30% methanol, and then eluted with 10 ml of methanol. The methanol solution was collected into a 10 ml volumetric flask and shaken to obtain.

色譜條件與系統適用性試驗：以十八烷基矽烷鍵合的矽膠為填充劑；乙腈為流動相A，水為流動相B，按照下表5進行梯度洗脫；流速為每分鐘1.0ml；檢測波長為203nm；柱溫30℃；記錄時間為75分鐘。 Chromatographic conditions and system suitability test: octadecyl decane bonded silicone as a filler; acetonitrile as mobile phase A, water as mobile phase B, gradient elution according to Table 5; flow rate of 1.0 ml per minute; The detection wavelength was 203 nm; the column temperature was 30 ° C; and the recording time was 75 minutes.

測定：分別精密吸取對照品溶液、供試品溶液各10μl，注入液相色譜儀，按上述條件進行測定，各組分保留時間見圖12。 Measurement: 10 μl of each of the reference solution and the test solution were accurately taken up, injected into a liquid chromatograph, and measured according to the above conditions. The retention time of each component is shown in FIG.

本發明中藥組合物的製備 Preparation of traditional Chinese medicine composition of the invention

實施例1 Example 1

取丹參藥材820g切成1-2cm的小段，將三七藥材160g粉碎成0.18cm顆粒；稱取藥材量2.25%的碳酸氫鈉；將稱量好的丹參、三七、碳酸氫鈉投入提取罐中，每罐加5倍量工藝用水，加熱煮沸，保持沸騰約2h，過濾，藥渣進行第二次提取，加入4倍量水，加熱煮沸，保持沸騰約1h，過濾，藥渣棄去；將提取液減壓濃縮至相對密度為1.16-1.20(80±5℃)或相應48-52%糖度，得濃縮液；濃縮液打入醇沉罐中，加入適量乙醇調至含醇量為65%~70%，靜置12小時，至沉澱完全，分離上清液，沉澱棄去；上清液濃縮即得浸膏，浸膏乾燥即得丹參三七提取物。 Take 820g of Salvia miltiorrhiza medicinal materials and cut into small pieces of 1-2cm, pulverize 160g of Radix Notoginseng into 0.18cm granules; weigh 2.25% of sodium bicarbonate; put the weighed Danshen, Sanqi and Sodium Bicarbonate into the extraction tank In the tank, add 5 times of process water per tank, heat to boil, keep boiling for about 2h, filter, dregs for the second extraction, add 4 times the amount of water, heat to boil, keep boiling for about 1h, filter, discard the drug residue; The extract is concentrated under reduced pressure to a relative density of 1.16 - 1.20 (80 ± 5 ° C) or a corresponding 48-52% sugar to obtain a concentrated liquid; the concentrated liquid is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 65. %~70%, let stand for 12 hours, until the precipitation is complete, separate the supernatant, and discard the precipitate; the supernatant is concentrated to obtain the extract, and the extract is dried to obtain the extract of Salvia miltiorrhiza.

丹參三七提取物按上述測定方法進行測定，其中，丹參三七提取物中含有丹參素36mg/g、丹酚酸T 11mg/g、原兒茶醛17mg/g、丹酚酸D 6mg/g、迷迭香酸7mg/g、丹酚酸B 13mg/g、丹酚酸A 9mg/g、三七皂苷R 17mg/g、人參皂苷Rg1 24mg/g、人參皂苷Re 3mg/g、人參皂苷Rb1 18mg/g、人參皂苷Rd 4mg/g、二氫丹參酮I 0.3mg/g、丹參酮I 0.7mg/g、隱丹參酮0.6mg/g、丹參酮IIA 2.7mg/g。 The extract of Salvia miltiorrhiza Bge. was determined according to the above determination method. Among them, Salvia miltiorrhiza extract contains Danshensu 36 mg/g, salvianolic acid T 11 mg/g, protocatechuic aldehyde 17 mg/g, salvianolic acid D 6 mg/g. , rosmarinic acid 7mg / g, salvianolic acid B 13mg / g, salvianolic acid A 9mg / g, notoginsenoside R 17mg / g, ginsenoside Rg1 24mg / g, ginsenoside Re 3mg / g, ginsenoside Rb1 18 mg/g, ginsenoside Rd 4 mg/g, dihydrotanshinone I 0.3 mg/g, tanshinone I 0.7 mg/g, cryptotanshinone 0.6 mg/g, and tanshinone IIA 2.7 mg/g.

取丹參三七提取物90g、冰片9g混合均勻，即得中藥組合物。 90 g of the extract of Salvia miltiorrhiza Bge. and 9 g of borneol were uniformly mixed to obtain a traditional Chinese medicine composition.

實施例2 Example 2

取實施例1中製備的丹參三七提取物75g、冰片25g，混合均勻勻，既得中藥組合物。 75 g of Salvia miltiorrhiza extract and 25 g of borneol prepared in Example 1 were mixed and uniformly mixed to obtain a traditional Chinese medicine composition.

實施例3 Example 3

將丹參800.0g、三七150.0g在鹼性條件下(pH=9)的水中煎煮3次，每次煎煮1小時，過濾，得濾液I，藥渣加水煎煮3次，每次1小時，濾過，得濾液II，將濾液I、II合併濃縮，濃縮液加入乙醇到醇濃度70%，靜置，取上清液，過濾，回收乙醇，濃縮乾燥得丹參三七提取物。 800.0 g of Salvia miltiorrhiza and 150.0 g of Panax notoginseng were boiled in water for 3 times under alkaline conditions (pH=9), and boiled for 1 hour each time. Filtration was carried out to obtain filtrate I, and the dregs were boiled 3 times with water, each time 1 After the filtration, the filtrate II was obtained, and the filtrates I and II were combined and concentrated. The concentrated liquid was added to ethanol to an alcohol concentration of 70%, and the mixture was allowed to stand. The supernatant was taken, filtered, and the ethanol was recovered and concentrated to obtain the extract of Salvia miltiorrhiza.

丹參三七提取物按上述測定方法進行測定，其中，丹參三七提取物中包括丹參素40mg/g、丹酚酸T 12mg/g、原兒茶醛20mg/g、丹酚酸D 7mg/g、迷迭香酸9mg/g、丹酚酸B 16mg/g、 丹酚酸A 12mg/g、三七皂苷R1 9mg/g、人參皂苷Rg1 28mg/g、人參皂苷Re 4mg/g、人參皂苷Rb1 22mg/g、人參皂苷Rd 6mg/g、二氫丹參酮I 0.4mg/g、丹參酮I 0.8mg/g、隱丹參酮0.6mg/g、丹參酮IIA 2.8mg/g。 The extract of Salvia miltiorrhiza Bge. was determined according to the above determination method. Among them, Danshen Sanqi extract includes Danshensu 40 mg/g, salvianolic acid T 12 mg/g, protocatechuic aldehyde 20 mg/g, and salvianolic acid D 7 mg/g. , rosmarinic acid 9mg / g, salvianolic acid B 16mg / g, Salvianolic acid A 12 mg/g, notoginsenoside R1 9 mg/g, ginsenoside Rg1 28 mg/g, ginsenoside Re 4 mg/g, ginsenoside Rb1 22 mg/g, ginsenoside Rd 6 mg/g, dihydrotanshinone I 0.4 mg /g, tanshinone I 0.8 mg / g, cryptotanshinone 0.6 mg / g, tanshinone IIA 2.8 mg / g.

取丹參三七提取物99.9g、冰片0.1g混合均勻，即得中藥組合物。 Take 99.9 g of Salvia miltiorrhiza extract and 0.1 g of borneol, and mix well to obtain a traditional Chinese medicine composition.

實施例4 Example 4

取實施例3製備的丹參三七提取物90g、冰片10g，混合均勻，既得中藥組合物。 90 g of Salvia miltiorrhiza extract and 10 g of borneol prepared in Example 3 were mixed and uniformly obtained to obtain a traditional Chinese medicine composition.

實施例5 Example 5

丹參750g、三七250g在鹼性條件下(pH=7.5)的水中煎煮2次，每次煎煮2小時，過濾，得濾液I，藥渣加水煎煮2次，每次2小時，過濾，得濾液II，將濾液I、II合併濃縮，向濃縮液中加入乙醇至醇濃度70%，靜置，取上清液，過濾，回收乙醇，濃縮乾燥得丹參三七提取物。 Salvia miltiorrhiza 750g and Panax notoginseng 250g were boiled twice in water under alkaline conditions (pH=7.5), boiled for 2 hours each time, filtered to obtain filtrate I, and the dregs were boiled twice with water for 2 hours each time. The filtrate II was obtained, and the filtrates I and II were combined and concentrated. To the concentrated liquid, ethanol was added to an alcohol concentration of 70%, and the mixture was allowed to stand. The supernatant was taken, filtered, and the ethanol was recovered and concentrated to obtain the extract of Salvia miltiorrhiza.

丹參三七提取物按上述測定方法進行測定，其中，丹參三七提取物中含有的丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、三七皂苷R1、人參皂苷Rg1、人參皂苷Re、人參皂苷Rb1、人參皂苷Rd、二氫丹參酮I、丹參酮I、隱丹參酮、丹參酮IIA的量分別為30mg/g、9mg/g、14mg/g、5mg/g、5mg/g、10mg/g、7mg/g、5mg/g、18mg/g、2mg/g、17mg/g、2mg/g、0.3mg/g、0.7mg/g、0.5mg/g、2.6mg/g。 The extract of Salvia miltiorrhiza Bge. is determined according to the above determination method, wherein Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, and the extract of Salvia miltiorrhiza Bge. The amounts of salvianolic acid A, notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA were 30 mg/g and 9 mg/g, respectively. , 14 mg / g, 5 mg / g, 5 mg / g, 10 mg / g, 7 mg / g, 5 mg / g, 18 mg / g, 2 mg / g, 17 mg / g, 2 mg / g, 0.3 mg / g, 0.7 mg / g , 0.5mg / g, 2.6mg / g.

取丹參三七提取物50g、冰片50g混合均勻，即得中藥組合物。 50g of Salvia miltiorrhiza extract and 50g of borneol were mixed uniformly to obtain a traditional Chinese medicine composition.

實施例6 Example 6

取實施例5製備的丹參三七提取物99g、冰片1g，混合均勻，既得中藥組合物。 The extract of Salvia miltiorrhiza Bge. prepared in Example 5 and 99 g of borneol were mixed and uniformly obtained, and a traditional Chinese medicine composition was obtained.

實施例7 Example 7

丹參83份、三七17份在鹼性條件下(pH=7.5)的水中煎煮2 次，每次煎煮2小時，過濾，得濾液I；藥渣加水煎煮2次，每次2小時，過濾，得濾液II；將濾液I、II合併濃縮，濃縮液加入乙醇至醇濃度70%，靜置，取上清液，過濾，回收乙醇，濃縮乾燥得丹參三七提取物；加入冰片1份混合均勻勻，既得中藥組合物。冰片從市場上購買得到。 83 parts of Salvia miltiorrhiza and 17 parts of Panax notoginseng are boiled in water under alkaline conditions (pH=7.5) 2 Next, each time of boiling for 2 hours, filtration, to obtain filtrate I; the dregs were boiled twice with water for 2 hours, and filtered to obtain filtrate II; the filtrates I and II were combined and concentrated, and the concentrate was added to ethanol to an alcohol concentration of 70. %, stand still, take the supernatant, filter, recover the ethanol, concentrate and dry to obtain the extract of Salvia miltiorrhiza Bge.; add 1 part of borneol and mix well to obtain the traditional Chinese medicine composition. Borneol is purchased from the market.

按上述測定方法進行測定，其中，丹參三七提取物中含有的丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、三七皂苷R1、人參皂苷Rg1、人參皂苷Re、人參皂苷Rb1、人參皂苷Rd、二氫丹參酮I、丹參酮I、隱丹參酮、丹參酮IIA的含量分別為40mg/g、12mg/g、20mg/g、7mg/g、9mg/g、16mg/g、12mg/g、9mg/g、28mg/g、4mg/g、22mg/g、6mg/g、0.4mg/g、0.8mg/g、0.6mg/g、2.8mg/g。 According to the above measurement method, Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, The contents of notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA are 40 mg/g, 12 mg/g, 20 mg/g, respectively. 7mg/g, 9mg/g, 16mg/g, 12mg/g, 9mg/g, 28mg/g, 4mg/g, 22mg/g, 6mg/g, 0.4mg/g, 0.8mg/g, 0.6mg/g , 2.8mg / g.

實施例8 Example 8

取丹參藥材400g切成1-2cm段，將三七藥材80g粉碎成顆粒；稱取藥材量3%的碳酸氫鈉，將稱量好的丹參、三七、碳酸氫鈉投入提取罐中，每罐加5倍量工藝用水，加熱煮沸，保持沸騰約2h±20min，過濾，藥渣進行第二次提取，加入4倍量水，加熱煮沸，保持沸騰約1h±15min，過濾，藥渣棄去；提取液減壓濃縮至相對密度為1.16-1.20(80±5℃)或相應50%糖度，得濃縮液；濃縮液打入醇沉罐中，加入適量乙醇調至含醇量為68%，靜置20小時，至沉澱完全，分離上清液，沉澱棄去；上清液濃縮即得浸膏，浸膏乾燥即得丹參三七提取物。 400g of Salvia miltiorrhiza var. chinensis was cut into 1-2cm sections, 80g of Sanqi medicinal material was pulverized into granules; 3% of sodium bicarbonate was weighed, and the weighed Danshen, Sanqi and Sodium Bicarbonate were put into the extraction tank. Add 5 times of process water to the tank, heat and boil, keep boiling for about 2h±20min, filter, the second extraction of the dregs, add 4 times of water, heat to boil, keep boiling for about 1h±15min, filter, discard and discard The extract is concentrated under reduced pressure to a relative density of 1.16 - 1.20 (80 ± 5 ° C) or a corresponding 50% sugar to obtain a concentrated liquid; the concentrated liquid is poured into an alcohol precipitation tank, and an appropriate amount of ethanol is added to adjust the alcohol content to 68%. After standing for 20 hours, until the precipitation is complete, the supernatant is separated, and the precipitate is discarded; the supernatant is concentrated to obtain an extract, and the extract is dried to obtain the extract of Salvia miltiorrhiza.

按照上述測定方法進行測定，其中，丹參三七提取物中含有丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、三七皂苷R1、人參皂苷Rg1、人參皂苷Re、人參皂苷Rb1、人參皂苷Rd、二氫丹參酮1、丹參酮I、隱丹參酮、丹參酮IIA含量分別為20mg/g、5mg/g、10mg/g、2mg/g、0.2mg/g、5mg/g、5mg/g、2mg/g、1mg/g、1mg/g、10mg/g、1mg/g、0.1mg/g、0.5mg/g、 0.2mg/g、1mg/g。 According to the above determination method, the Danshen Sanqi extract contains Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, three The contents of heptapeptide R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone 1, tanshinone I, cryptotanshinone, and tanshinone IIA were 20 mg/g, 5 mg/g, 10 mg/g, 2 mg/, respectively. g, 0.2 mg/g, 5 mg/g, 5 mg/g, 2 mg/g, 1 mg/g, 1 mg/g, 10 mg/g, 1 mg/g, 0.1 mg/g, 0.5 mg/g, 0.2 mg/g, 1 mg/g.

取丹參三七提取物90g、冰片10g混合均勻，即得中藥組合物， Take 90g of Salvia miltiorrhiza extract and 10g of borneol to form a traditional Chinese medicine composition.

實施例9 Example 9

取丹參藥材500g切1-2cm段，將三七藥材102g粉碎成顆粒，稱取藥材量2.5%的碳酸氫鈉，將稱量好的丹參、三七、碳酸氫鈉投入提取罐中，每罐加6倍量工藝用水，加熱煮沸，保持沸騰約2h，過濾，藥渣進行第二次提取，加入6倍量水，加熱煮沸，保持沸騰約1h，過濾，藥渣棄去；提取液減壓濃縮至相對密度為1.16-1.20(80±5℃)或相應48%糖度，得濃縮液；濃縮液打入醇沉罐中，加入適量乙醇調至含醇量為65%，靜置24小時，至沉澱完全，分離上清液，沉澱棄去；上清液濃縮即得浸膏，浸膏乾燥即得丹參三七提取物。 Take 500g of Salvia miltiorrhiza sinensis and cut 1-2cm section, smash 102g of Sanqi medicinal material into granules, weigh 2.5% sodium bicarbonate, and put the weighed Danshen, Sanqi and Sodium Bicarbonate into the extraction tank. Add 6 times the amount of process water, heat to boil, keep boiling for about 2h, filter, dregs for the second extraction, add 6 times the amount of water, heat to boil, keep boiling for about 1h, filter, discard the drug residue; extract liquid decompression Concentrate to a relative density of 1.16 - 1.20 (80 ± 5 ° C) or a corresponding 48% sugar, to obtain a concentrated solution; the concentrate is poured into an alcohol precipitation tank, added with an appropriate amount of ethanol to adjust the alcohol content to 65%, and allowed to stand for 24 hours. Until the precipitation is complete, the supernatant is separated, and the precipitate is discarded; the supernatant is concentrated to obtain an extract, and the extract is dried to obtain the extract of Salvia miltiorrhiza.

按照上述測定方法進行測定，其中，丹參三七提取物中含有的丹參素、丹酚酸T、原兒茶醛、丹酚酸D、迷迭香酸、丹酚酸B、丹酚酸A、三七皂苷R1、人參皂苷Rg1、人參皂苷Re、人參皂苷Rb1、人參皂苷Rd、二氫丹參酮I、丹參酮I、隱丹參酮、丹參酮IIA的含量分別為60mg/g、20mg/g、30mg/g、10mg/g、10mg/g、20mg/g、20mg/g、10mg/g、40mg/g、5mg/g、40mg/g、10mg/g、0.5mg/g、1mg/g、1mg/g、5mg/g。 According to the above measurement method, Danshensu, salvianolic acid T, protocatechuic aldehyde, salvianolic acid D, rosmarinic acid, salvianolic acid B, salvianolic acid A, The contents of notoginsenoside R1, ginsenoside Rg1, ginsenoside Re, ginsenoside Rb1, ginsenoside Rd, dihydrotanshinone I, tanshinone I, cryptotanshinone, and tanshinone IIA are 60 mg/g, 20 mg/g, 30 mg/g, respectively. 10 mg/g, 10 mg/g, 20 mg/g, 20 mg/g, 10 mg/g, 40 mg/g, 5 mg/g, 40 mg/g, 10 mg/g, 0.5 mg/g, 1 mg/g, 1 mg/g, 5 mg /g.

取丹參三七提取物99.9g、冰片0.1g混合均勻，即得中藥組合物。 Take 99.9 g of Salvia miltiorrhiza extract and 0.1 g of borneol, and mix well to obtain a traditional Chinese medicine composition.

本發明藥物製劑的製備 Preparation of pharmaceutical preparation of the invention

實施例10 Example 10

取實施例1-9任意一項所述的中藥組合物0.5g與PEG-600010.5g混合均勻，加熱熔融，化料後移至滴丸滴灌中，藥液滴至6~8℃液體石蠟中，除油，製得滴丸400粒。 0.5g of the traditional Chinese medicine composition according to any one of the embodiments 1-9 is uniformly mixed with PEG-600010.5g, heated and melted, and then transferred to a drip irrigation drip irrigation, and the medicine drops to liquid paraffin at 6-8 ° C. Degreasing, made 400 pills.

實施例11 Example 11

取實施例1-9任意一項所述的中藥組合物0.5g、葡萄糖4.5g、 硫代硫酸鈉0.9g和蒸餾水1ml，上述組分混合均勻後，冷凍乾燥，分裝500支，即得。 The traditional Chinese medicine composition according to any one of Examples 1 to 9 is 0.5 g, and the glucose is 4.5 g. 0.9 g of sodium thiosulfate and 1 ml of distilled water, the above components were uniformly mixed, freeze-dried, and 500 parts were obtained.

實施例12 Example 12

取實施例1-9任意一項所述的中藥組合物0.5g、甘露醇5.5g、依地酸鈣鈉0.9g和蒸餾水2ml，上述組分混勻後，冷凍乾燥，分裝300支，即得。 Take 0.5g of the traditional Chinese medicine composition according to any one of Examples 1-9, 5.5g of mannitol, 0.9g of sodium edetate and 2ml of distilled water. After mixing the above components, freeze-dry and dispense 300 pieces. Got it.

實施例13 Example 13

取實施例1-9任意一項所述的中藥組合物0.5g、澱粉50g、蔗糖50g，上述組分混勻後，製粒，壓片即得片劑。 0.5 g of the traditional Chinese medicine composition according to any one of Examples 1-9, 50 g of starch, and 50 g of sucrose, and the above components were mixed, granulated, and tablets were obtained by tableting.

實施例14 Example 14

取實施例1-9任意一項所述的中藥組合物0.5g、澱粉50g、蔗糖50g，上述組分混勻後，製粒，裝膠囊即得膠囊劑。 0.5 g of the traditional Chinese medicine composition according to any one of the examples 1-9, 50 g of starch, and 50 g of sucrose, and the above components are mixed, granulated, and capsules are obtained by capsule filling.

本發明複方丹參微滴丸的製備 Preparation of compound Danshen micro-drop pills of the invention

實施例15 Example 15

取實施例1製得的中藥組合物82.5g、PEG-6000 165g。 82.5 g of the traditional Chinese medicine composition prepared in Example 1 and 165 g of PEG-6000 were obtained.

(1)預混步驟：將中藥組合物加水預混，40±10℃保溫罐內攪拌60min以上，使中藥組合物的含水量為13.0wt%，得到中藥組合物預混料，備用。 (1) Premixing step: premixing the traditional Chinese medicine composition with water, stirring in a 40±10°C incubator for more than 60 minutes, so that the water content of the traditional Chinese medicine composition is 13.0% by weight, and the premix of the traditional Chinese medicine composition is obtained, and used.

(2)化料步驟：先將PEG-6000加入化料罐中，加熱至90℃，預先熔融，再加入中藥組合物預混料，採用低速均質(3200rpm)混合物料，混合完成後，提高均質速度至5000rpm進行化料，時間6min，在化料過程中，物料的溫度保持在80±5℃。由此，得到熔融藥液。 (2) Chemical step: first add PEG-6000 to the chemical tank, heat to 90 ° C, pre-melt, and then add the Chinese medicine composition premix, using low-speed homogeneous (3200 rpm) mixture, after mixing, improve homogenization The material was subjected to a speed of 5000 rpm for 6 minutes, and the temperature of the material was maintained at 80 ± 5 ° C during the chemical process. Thereby, a molten chemical liquid is obtained.

(3)滴製步驟：將上述熔融藥液輸送至滴頭，調節滴頭的振動頻率為137Hz，滴頭溫度控制在80℃，藥液通過加壓方式(滴製壓力1.8Bar)流入滴頭，並從滴頭底部振動滴出，滴製速度與步驟(1)化料速度匹配。 (3) Drip step: the above molten liquid is transported to the dripper, the vibration frequency of the dripper is adjusted to 137 Hz, the dripper temperature is controlled at 80 ° C, and the drug solution flows into the dripper by a pressurization method (dropping pressure of 1.8 Bar). And vibrating from the bottom of the dripper, the dropping speed is matched with the speed of the step (1).

(4)冷凝步驟：滴出的藥滴到冷卻管道中，採用低溫惰性氣 體冷卻，冷卻溫度-115±5℃，使滴出的藥液冷卻成固態滴丸。 (4) Condensation step: the dripping medicine drops into the cooling pipe, using low temperature inert gas The body is cooled, and the cooling temperature is -115 ± 5 ° C, so that the dripped liquid is cooled to a solid drop.

(5)乾燥步驟：將所述滴丸進行流化乾燥，待物料在床體內形成較好的流態後，升溫至25℃乾燥60min，再升溫至45℃乾燥30min，繼續升溫至55℃乾燥30min，然後降溫至30℃以下出料。將滴丸水分控制在3.0~7.0wt%，得到中間體素丸。 (5) Drying step: the dropping pill is fluidized and dried, and after the material forms a better flow state in the bed, the temperature is raised to 25 ° C for 60 min, then the temperature is raised to 45 ° C for 30 min, and the temperature is further increased to 55 ° C. 30 min, then cooled to below 30 ° C discharge. The water content of the dropping pill is controlled at 3.0 to 7.0 wt% to obtain an intermediate pill.

(6)包衣步驟：按照包衣投料量和處方計算包衣粉用量，取素丸重量的4%的歐巴代配製成濃度為18wt%的包衣液，攪拌45min。設定進風溫度為25℃，將合格素丸投入流化床後，提高設定進風溫度至48℃，待物料溫度達到38℃後，開始包衣。包衣過程中物料溫度控制在35~45℃，包衣完成後降溫至30℃以下出料，篩丸，得到中間體包衣丸。將中間體包衣丸的增重控制在3.3±0.7wt%，水分控制在3.0~7.0wt%。 (6) Coating step: Calculate the amount of coating powder according to the amount of coating and the dosage of the coating, and prepare 4% of the weight of the granules to prepare a coating liquid having a concentration of 18% by weight, and stir for 45 minutes. The inlet air temperature was set to 25 ° C, and after the qualified pellets were put into the fluidized bed, the set inlet air temperature was raised to 48 ° C, and after the material temperature reached 38 ° C, the coating was started. During the coating process, the temperature of the material is controlled at 35~45 °C. After the coating is completed, the temperature is lowered to below 30 °C, and the pellets are obtained to obtain the intermediate coated pellets. The weight gain of the intermediate coated pellets was controlled at 3.3 ± 0.7 wt%, and the moisture was controlled at 3.0 to 7.0 wt%.

(7)制膠囊、包裝步驟：將製成粒徑為1.0mm~2.0mm滴丸進行膠囊裝填，並通過膠囊檢重機完成100%線上檢重，然後包裝成最終產品。 (7) Capsule and packaging steps: Capsules with a particle size of 1.0 mm to 2.0 mm are prepared for capsule filling, and 100% on-line weight is checked by a capsule weighing machine, and then packaged into a final product.

其中，滴製過程中，滴丸成形情況通過頻閃照射加目測，可進行即時線上監控及調整；在載藥包衣後，為提高滴丸粒徑均勻度及圓整度，還可加入篩丸整粒步驟。 Among them, in the process of dropping, the forming of the dropping pills can be monitored and adjusted on-line by stroboscopic irradiation and visual inspection; after the drug-loading coating, in order to improve the uniformity and roundness of the particle size of the dropping pills, a sieve can be added. Pill granules step.

實施例16 Example 16

除所述中藥組合物與PEG-6000的重量比為1：5外，其他與實施例15相同，製備複方丹參微滴丸。 Compound Danshen microdroplets were prepared in the same manner as in Example 15 except that the weight ratio of the traditional Chinese medicine composition to PEG-6000 was 1:5.

實施例17 Example 17

除所述中藥組合物與PEG-6000的重量比為5：1外，其他與實施例15相同，製備複方丹參微滴丸。 Compound Danshen microdroplets were prepared in the same manner as in Example 15 except that the weight ratio of the traditional Chinese medicine composition to PEG-6000 was 5:1.

實施例18 Example 18

取實施例1製得的中藥組合物82.5g，環糊精和瓊脂1：1的混合物165g，製備成微滴丸，製備方法如下：(1)化料步驟：將中藥組合物與作為滴丸基質的環糊精和瓊 脂1：1的混合物投入到均質機中，以1000rpm均質混合，時間1min，然後，以3000rpm均質化料，時間1min，在化料過程中，物料的溫度保持在60℃，由此得到熔融藥液；(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度70℃、滴製振動頻率50Hz、滴製壓力為0.5Bar的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配；(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm的滴丸素丸，所述冷卻氣體的溫度為0℃。 82.5 g of the traditional Chinese medicine composition prepared in Example 1 and 165 g of a mixture of cyclodextrin and agar 1:1 were prepared into micro-drop pellets, and the preparation method was as follows: (1) Chemical step: using a traditional Chinese medicine composition as a dropping pill Matrix of cyclodextrin and jon The mixture of lipid 1:1 was put into a homogenizer, homogenized and mixed at 1000 rpm for 1 min, and then homogenized at 3000 rpm for 1 min. During the chemical process, the temperature of the material was maintained at 60 ° C, thereby obtaining a molten drug. (2) Drip step: the above molten liquid is transported to the dripper, and the dripper is shaken at a temperature of 70 ° C, the vibration frequency is 50 Hz, and the dropping pressure is 0.5 Bar. The speed is matched with the step (1) the material speed; (3) the condensation step: the dripped medicine droplet is rapidly cooled in the cooling gas, and solidified into a pill pellet having a particle diameter of 0.2 mm, and the temperature of the cooling gas is 0 ° C.

實施例19 Example 19

取實施例1製得的中藥組合物82.5g，***膠和乳糖=1：1的混合物165g，製備成複方丹參微滴丸，製備方法如下：(1)化料步驟：將中藥組合物與作為滴丸基質的***膠和乳糖1：1的混合物投入到均質機中，以5000rpm均質混合，時間200min，然後，以10000rpm均質化料，時間100min，在化料過程中，物料的溫度保持在100℃，由此得到熔融藥液；(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度300℃、滴製振動頻率為300Hz、滴製壓力為4.0Bar的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配；(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為4.0mm的滴丸素丸，所述冷卻氣體的溫度為-150℃。 82.5 g of the traditional Chinese medicine composition prepared in Example 1 and 165 g of a mixture of gum arabic and lactose=1:1 were prepared into compound Danshen microdroplets, and the preparation method was as follows: (1) Chemical step: the traditional Chinese medicine composition was used as The 1:1 mixture of gum arabic and lactose was put into a homogenizer, homogenized and mixed at 5000 rpm for 200 min, then homogenized at 10,000 rpm for 100 min. During the chemical process, the temperature of the material was kept at 100. °C, thereby obtaining a molten chemical solution; (2) a dropping step: delivering the molten chemical solution to the dripper at a dripper temperature of 300 ° C, a dropping vibration frequency of 300 Hz, and a dropping pressure of 4.0 Bar. After the drip vibrating drop, the dropping speed is matched with the step (1) the material speed; (3) the condensation step: the dripped medicine droplet is rapidly cooled in the cooling gas, and solidified into a dropping pill having a particle diameter of 4.0 mm. The temperature of the cooling gas is -150 °C.

實施例20 Example 20

取實施例1製得的中藥組合物82.5g，乳糖醇165g，製備成複方丹參微滴丸，製備方法如下： 82.5 g of the traditional Chinese medicine composition prepared in Example 1 and 165 g of lactitol were prepared into a compound Danshen micro-drop pellet, and the preparation method was as follows:

(1)化料步驟：將中藥組合物與作為滴丸基質的乳糖醇投入到均質機中，以2500rpm均質混合，時間100min，然後，以6000rpm均質化料，時間50min，在化料過程中，物料的溫度保持在80℃，由此得到熔融藥液； (1) Chemical step: the traditional Chinese medicine composition and the lactitol as the dropping pill matrix are put into a homogenizer, homogenized and mixed at 2500 rpm for 100 min, and then homogenized at 6000 rpm for 50 min, during the chemical process, The temperature of the material is maintained at 80 ° C, thereby obtaining a molten chemical solution;

(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度150 ℃、滴製振動頻率150Hz、滴製壓力為2Bar的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配； (2) Driping step: delivering the above molten liquid to the dripper at a dripper temperature of 150 °C, the vibration frequency of 150Hz, the dropping pressure is 2Bar, the drip vibration is dripped, and the dropping speed is matched with the step (1) chemical speed;

(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為2mm的滴丸素丸，所述冷卻氣體的溫度為-100℃。 (3) Condensation step: The dropped drug droplets were rapidly cooled in a cooling gas to be solidified into pellets having a particle diameter of 2 mm, and the temperature of the cooling gas was -100 °C.

(4)乾燥步驟：將所述滴丸採用流化乾燥設備進行流化乾燥，於50℃乾燥2h，得乾燥滴丸素丸。 (4) Drying step: the dropping pills are fluidized and dried by a fluidized drying device, and dried at 50 ° C for 2 hours to obtain dried dropping pills.

(5)包衣步驟：所述乾燥滴丸素丸在流化床中包衣，包衣材料與素丸重量比為1：25，包衣液濃度為10wt%，於溫度40℃進行包衣，得包衣滴丸，包衣材料為歐巴代。 (5) Coating step: the dried dropping pills are coated in a fluidized bed, the weight ratio of the coating material to the pellet is 1:25, the concentration of the coating liquid is 10% by weight, and the coating is carried out at a temperature of 40 ° C. , coated with pills, the coating material is Opadry.

實施例21 Example 21

取實施例1製得的中藥組合物82.5g，PEG8000 165g，製備成複方丹參微滴丸，製備方法如下：將上述中藥組合物粉末加水後，於60℃攪拌10min以上，得到中藥組合物預混料。 82.5 g of the traditional Chinese medicine composition prepared in Example 1 and 165 g of PEG 8000 were prepared into a compound Danshen micro-drop pellet. The preparation method was as follows: after adding the water of the above-mentioned traditional Chinese medicine composition powder, stirring at 60 ° C for 10 min or more, the Chinese medicine composition was premixed. material.

(1)化料步驟：將上述中藥組合物預混料與PEG-8000投入到均質機中，以2500rpm均質混合，時間100min，然後，以6000rpm均質化料，時間50min，在化料過程中，物料的溫度保持在80℃，得熔融藥液。 (1) Chemical step: the above traditional Chinese medicine composition premix and PEG-8000 are put into a homogenizer, homogenized and mixed at 2500 rpm for 100 min, then homogenized at 6000 rpm for 50 min, during the chemical process, The temperature of the material was maintained at 80 ° C to obtain a molten chemical.

(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度150℃、滴製振動頻率150Hz、滴製壓力為2Bar的條件下，經滴頭振動滴製，滴製速度與步驟(1)化料速度匹配。 (2) Driping step: the above molten liquid is transported to the dripper, and the dripper is dripped at a dripper temperature of 150 ° C, a drip vibration frequency of 150 Hz, and a dropping pressure of 2 Bar. Step (1) The material speed is matched.

(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為2mm的滴丸素丸，所述冷卻氣體的溫度為-100℃。 (3) Condensation step: The dropped drug droplets were rapidly cooled in a cooling gas to be solidified into pellets having a particle diameter of 2 mm, and the temperature of the cooling gas was -100 °C.

(4)乾燥步驟：將所述滴丸採用流化乾燥設備進行流化乾燥，於50℃乾燥2h，得乾燥滴丸素丸。 (4) Drying step: the dropping pills are fluidized and dried by a fluidized drying device, and dried at 50 ° C for 2 hours to obtain dried dropping pills.

(5)包衣步驟：所述乾燥滴丸素丸在流化床中包衣，包衣材料與素丸重量比為1：25，包衣液濃度為10wt%，於溫度40℃進行包衣，得包衣滴丸，包衣材料蟲膠。 (5) Coating step: the dried dropping pills are coated in a fluidized bed, the weight ratio of the coating material to the pellet is 1:25, the concentration of the coating liquid is 10% by weight, and the coating is carried out at a temperature of 40 ° C. , get coated pills, coated material shellac.

實施例22 Example 22

取實施例1製得的中藥組合物92g、PEG-1000 270g，製備成複方丹參微滴丸，製備方法如下：將中藥組合物粉末加水後，於30℃攪拌10min以上，得到藥物預混料。 92 g of the traditional Chinese medicine composition prepared in Example 1 and 270 g of PEG-1000 were prepared to prepare a compound Danshen micro-drop pellet. The preparation method was as follows: after adding water to the powder of the traditional Chinese medicine composition, the mixture was stirred at 30 ° C for 10 minutes or more to obtain a drug premix.

(1)化料步驟：將上述中藥組合物與PEG-1000投入到均質機中，以2500rpm均質混合，時間100min，然後，以6000rpm均質化料，時間20min，在化料過程中，物料的溫度保持在100℃，得熔融藥液。 (1) Chemical step: the above traditional Chinese medicine composition and PEG-1000 are put into a homogenizer, and mixed at 2500 rpm for 100 min, then homogenized at 6000 rpm for 20 min, during the process of the material, the temperature of the material The solution was kept at 100 ° C to obtain a molten chemical.

(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度70℃、滴製振動頻率100Hz、滴製壓力為1.0Bar、加速度1G，滴製速度10Kg/h的條件下，經滴頭振動滴製，上述滴製速度與步驟(1)化料速度匹配。 (2) Drip step: the above molten liquid is transported to the dripper at a dripper temperature of 70 ° C, a dropping vibration frequency of 100 Hz, a dropping pressure of 1.0 Bar, an acceleration of 1 G, and a dropping speed of 10 kg/h. The dropping speed is matched with the speed of the step (1) by the vibration dripping of the drip head.

(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為2mm的滴丸素丸，所述冷卻氣體的溫度為-80℃。 (3) Condensation step: The dropped drug droplets were rapidly cooled in a cooling gas to be solidified into pellets having a particle diameter of 2 mm, and the temperature of the cooling gas was -80 °C.

(4)乾燥步驟：將所述滴丸採用梯度升溫乾燥法乾燥，-20℃形成流化態，於15℃乾燥10min，於35℃乾燥10min，於55℃乾燥30min，得乾燥滴丸素丸。 (4) Drying step: drying the dropping pellets by gradient heating, forming a fluidized state at -20 ° C, drying at 15 ° C for 10 min, drying at 35 ° C for 10 min, drying at 55 ° C for 30 min, and obtaining dried pills. .

(5)包衣步驟：所述乾燥滴丸素丸在流化床中包衣，包衣材料與素丸重量比為1：25，包衣液濃度為10wt%，於溫度40℃進行包衣，得包衣滴丸，包衣材料為苯二甲酸醋酸纖維素。 (5) Coating step: the dried dropping pills are coated in a fluidized bed, the weight ratio of the coating material to the pellet is 1:25, the concentration of the coating liquid is 10% by weight, and the coating is carried out at a temperature of 40 ° C. , coated with pills, the coating material is cellulose acetate phthalate.

實施例23 Example 23

取實施例1製得的中藥組合物105g、PEG-4000和PEG-6000 1：1的組合35g，製備成複方丹參微滴丸，製備方法如下：將中藥組合物粉末加水後，於80℃攪拌10min以上，得到中藥組合物預混料。 Taking the combination of 105g of the traditional Chinese medicine composition prepared in Example 1, 35g of PEG-4000 and PEG-6000 1:1, the compound Danshen micro-dropping pellet was prepared as follows: the Chinese medicine composition powder was added with water and then stirred at 80 ° C. For more than 10 minutes, a premix of the traditional Chinese medicine composition is obtained.

(1)化料步驟：將中藥組合物預混料與PEG-4000和PEG-6000 1：1的組合投入到均質機中，以2500rpm均質混合，時 間100min，然後，以6000rpm均質化料，時間80min，在化料過程中，物料的溫度保持在80℃，得熔融藥液。 (1) Chemical step: the Chinese medicine composition premix is put into a homogenizer in combination with PEG-4000 and PEG-6000 1:1, and homogeneously mixed at 2500 rpm. After 100 min, then, the material was homogenized at 6000 rpm for 80 min. During the chemical process, the temperature of the material was maintained at 80 ° C to obtain a molten chemical solution.

(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度100℃、滴製振動頻率200Hz、滴製壓力為3.0Bar、加速度20G、滴製速度40Kg/h的條件下，經滴頭振動滴製，上述滴製速度與步驟(1)化料速度匹配。 (2) Driping step: the molten liquid is transported to the dripper at a dripper temperature of 100 ° C, a dropping vibration frequency of 200 Hz, a dropping pressure of 3.0 Bar, an acceleration of 20 G, and a dropping speed of 40 Kg/h. The dropping speed is matched with the speed of the step (1) by the vibration dripping of the drip head.

(3)冷凝步驟：滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為2mm的滴丸素丸，所述冷卻氣體的溫度為-120℃。 (3) Condensation step: The dropped drug droplets were rapidly cooled in a cooling gas to be solidified into pellets having a particle diameter of 2 mm, and the temperature of the cooling gas was -120 °C.

(4)乾燥步驟：將所述滴丸採用梯度升溫乾燥法乾燥，30℃形成流化態，於35℃乾燥120min，於55℃乾燥60min，於100℃乾燥60min，得乾燥滴丸素丸。 (4) Drying step: the dropping pills are dried by a gradient heating method, formed into a fluidized state at 30 ° C, dried at 35 ° C for 120 min, dried at 55 ° C for 60 min, and dried at 100 ° C for 60 min to obtain dried pill pills.

(5)包衣步驟：所述乾燥滴丸素丸在流化床中包衣，包衣材料與素丸重量比為1：25，包衣液濃度為10wt%，於溫度35℃進行包衣，得包衣滴丸，包衣材料是丙烯酸甲酯。 (5) Coating step: the dried dropping pills are coated in a fluidized bed, the weight ratio of the coating material to the pellets is 1:25, the concentration of the coating liquid is 10% by weight, and the coating is carried out at a temperature of 35 ° C. , coated with pills, the coating material is methyl acrylate.

實施例24 Example 24

取實施例1製得的中藥組合物600g、冰片5g以及滴丸基質木糖醇600g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 600 g of the dropping base xylitol were taken.

(1)化料步驟：先將木糖醇加入化料罐中，加熱至90℃，預先熔融，再加入中藥組合物，混合均勻成熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭，滴頭採用蒸汽夾套保溫，在滴頭溫度為40℃、滴製振動頻率為50Hz的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-20℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥、包衣步驟：將冷卻後的固態滴丸進行流化乾燥及載藥包衣，乾燥溫度為75℃，製成粒徑為0.2mm~1.0mm的包衣微滴丸；(5)包裝步驟：將所述包衣微滴丸進行膠囊裝填，並通過膠 囊檢重機完成100%線上檢重，然後包裝成最終產品，滴丸粒徑0.2~1.0mm。 (1) Chemical step: first adding xylitol to the chemical tank, heating to 90 ° C, pre-melting, adding the traditional Chinese medicine composition, mixing and forming into a molten liquid; (2) dropping step: the above molten medicine The liquid is delivered to the dripper by pressurization, and the dripper is insulated by a steam jacket, and the molten liquid is flowed into the dripper under the condition that the dripper temperature is 40 ° C and the vibration frequency is 50 Hz, and the dripper is dripped from the dripper. (3) Condensation step: the dripping drug drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is -20 ° C, so that the dripped liquid is cooled into a solid dropping pill; (4) drying, wrapping Coating step: the cooled solid pellet is subjected to fluidized drying and drug-loading coating, and the drying temperature is 75 ° C to prepare a coated micro-droplet having a particle diameter of 0.2 mm to 1.0 mm; (5) packaging step: The coated micro-drop pellets are filled with capsules and passed through a gel The bag inspection machine completes 100% on-line checkweighing and then packages it into the final product. The particle size of the drop is 0.2~1.0mm.

其中，在滴製過程中，滴丸成形情況通過頻閃照射加目測，可進行即時線上監控及調整；在載藥包衣後，為提高滴丸的粒徑均勻度及圓整度，還可加入篩丸整粒步驟。 Among them, in the process of dropping, the forming of the dropping pills can be monitored and adjusted on the spot by stroboscopic irradiation and visual inspection; after the drug-loading coating, in order to improve the uniformity and roundness of the particle diameter of the dropping pills, Add the sieve pelleting step.

實施例25 Example 25

取實施例1製得的中藥組合物600g、冰片5g以及PEG-6000和PEG-4000滴丸基質3000g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 3000 g of PEG-6000 and PEG-4000 dropping base were taken.

(1)化料步驟：先將PEG-6000和PEG-4000加入化料罐中，加熱至120℃，預先熔融，再加入中藥組合物，混合均勻成熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭，滴頭採用蒸汽夾套保溫，在滴頭溫度為80℃、滴製振動頻率為20Hz的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-80℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥、包衣步驟：將冷卻後的固態滴丸進行流化乾燥及載藥包衣，乾燥溫度為150℃，製成粒徑為0.5mm~1.0mm的包衣微滴丸；(5)包裝步驟：將所述包衣微滴丸進行膠囊裝填，並通過膠囊檢重機完成100%線上檢重，然後包裝成最終產品。 (1) Chemical step: firstly add PEG-6000 and PEG-4000 to the chemical tank, heat to 120 ° C, pre-melt, then add the traditional Chinese medicine composition, and mix to form a molten liquid; (2) Drip step: The molten chemical solution is delivered to the dripper by pressurization, and the dripper is insulated by a steam jacket, and the molten liquid is flowed into the dripper under the condition that the dripper temperature is 80 ° C and the dropping vibration frequency is 20 Hz. And dripping from the bottom of the dripper; (3) Condensation step: the dripping drug drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is -80 ° C, so that the dripped liquid is cooled into a solid drop pill; (4 Drying and coating step: the cooled solid pellet is subjected to fluidized drying and drug-loading coating, and the drying temperature is 150 ° C to prepare a coated micro-droplet having a particle diameter of 0.5 mm to 1.0 mm; (5) Packing step: the coated micro-drop pellets are capsule-filled, and 100% on-line check weight is completed by a capsule weighing machine, and then packaged into a final product.

其中，在滴製過程中，滴丸成形情況通過頻閃照射加目測，可進行即時線上監控及調整；在載藥包衣後，為提高滴丸的粒徑均勻度及圓整度，還可加入篩丸整粒步驟。 Among them, in the process of dropping, the forming of the dropping pills can be monitored and adjusted on the spot by stroboscopic irradiation and visual inspection; after the drug-loading coating, in order to improve the uniformity and roundness of the particle diameter of the dropping pills, Add the sieve pelleting step.

實施例26 Example 26

取實施例1製得的中藥組合物600g、冰片5g以及PEG-1000滴丸基質120g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 120 g of a PEG-1000 dropping base were taken.

(1)化料步驟：先將PEG-1000加入化料罐中，加熱至40℃， 預先熔融，再加入中藥組合物，混合均勻成熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭，滴頭採用蒸汽夾套保溫，在滴頭溫度為40~60℃，滴製振動頻率為200Hz的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-100℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥、包衣步驟：將冷卻後的固態滴丸進行流化乾燥及載藥包衣，20℃形成流化態，25℃乾燥60min，45℃乾燥30min，55℃乾燥30min，製成粒徑為3.0mm~4.0mm的包衣微滴丸；(5)包裝步驟：將所述包衣微滴丸進行膠囊裝填，並通過膠囊檢重機完成100%線上檢重，然後包裝成最終產品。 (1) Chemical step: first add PEG-1000 to the chemical tank, and heat to 40 ° C. Pre-melted, and then added to the traditional Chinese medicine composition, and uniformly mixed into a molten chemical solution; (2) Driping step: the molten liquid is transported to the dripper by pressurization, and the dripper is insulated by a steam jacket, and the temperature at the dripper is 40~60 ° C, the dropping vibration frequency is 200 Hz, the molten liquid is poured into the dripper and dripped from the bottom of the dripper; (3) the condensation step: the dripping drug drops are used in the cooling pipe at a low temperature The inert gas is cooled, the cooling temperature is -100 ° C, and the dripped liquid is cooled to a solid drop pill; (4) drying, coating step: fluidized drying of the cooled solid pill and drug-loading coating, 20 °C is formed into a fluidized state, dried at 25 ° C for 60 min, dried at 45 ° C for 30 min, and dried at 55 ° C for 30 min to prepare coated micro-droplets having a particle size of 3.0 mm to 4.0 mm; (5) Packaging step: the coating micro The dropping pills are filled in capsules, and 100% on-line weight checking is performed by a capsule weighing machine, and then packaged into a final product.

其中，在滴製過程中，滴丸成形情況通過頻閃照射加目測，可進行即時線上監控及調整；在載藥包衣後，為提高滴丸的粒徑均勻度及圓整度，還可加入篩丸整粒步驟。 Among them, in the process of dropping, the forming of the dropping pills can be monitored and adjusted on the spot by stroboscopic irradiation and visual inspection; after the drug-loading coating, in order to improve the uniformity and roundness of the particle diameter of the dropping pills, Add the sieve pelleting step.

實施例27 Example 27

取實施例1製得的中藥組合物600g、冰片5g以及PEG-6000、PEG-4000滴丸基質3000g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 3000 g of PEG-6000 and PEG-4000 dropping base were taken.

(1)化料步驟：先將PEG-6000和PEG-4000加入化料罐中，加熱至120℃，預先熔融，再加入中藥組合物，投入均質機中，以1000rpm均質混合，時間1min，然後，以3000rpm均質化料，時間1min，在化料過程中，物料的溫度保持在60℃，得熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭，滴頭採用蒸汽夾套保溫，在滴頭溫度為70℃，滴製振動頻率為50Hz、滴製壓力為0.5Bar的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度0℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥、包衣步驟：將冷卻後的固態滴丸進行流化乾燥及 載藥包衣，乾燥溫度為150℃，製成粒徑為0.2mm的包衣微滴丸；(5)包裝步驟：將所述包衣微滴丸進行膠囊裝填，並通過膠囊檢重機完成100%線上檢重，然後包裝成最終產品。 (1) Chemical step: first add PEG-6000 and PEG-4000 to the chemical tank, heat to 120 ° C, pre-melt, then add the traditional Chinese medicine composition, put into the homogenizer, mix homogeneously at 1000 rpm for 1 min, then The material is homogenized at 3000 rpm for 1 min. During the chemical process, the temperature of the material is maintained at 60 ° C to obtain a molten chemical solution; (2) the dropping step: the molten liquid is transferred to the dripper by pressurization. The dripper is insulated by a steam jacket, and the molten liquid is poured into the dripper and dripped from the bottom of the dripper under the condition that the dripper temperature is 70 ° C, the vibration frequency is 50 Hz, and the dropping pressure is 0.5 Bar. (3) Condensation step: the dripping drug drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is 0 ° C, so that the dripped liquid is cooled into a solid drop pill; (4) drying, coating step: Cooled solid pellets for fluidized drying and The drug-loading coating is dried at a temperature of 150 ° C to prepare a coated micro-droplet pellet having a particle diameter of 0.2 mm; (5) a packaging step: the coated micro-droplet is filled into a capsule and completed by a capsule weighing machine. % check the weight on the line and pack it into the final product.

實施例28 Example 28

取實施例1製得的中藥組合物600g、冰片5g以及PEG-6000滴丸基質1800g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 1800 g of a PEG-6000 dropping base were taken.

(1)化料步驟：先將PEG-6000加入化料罐中，加熱至120℃，預先熔融，再加入中藥組合物，投入均質機中，以5000rpm均質混合，時間200min，然後，以10000rpm均質化料，時間1min，在化料過程中，物料的溫度保持在100℃，得熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭，滴頭採用蒸汽夾套保溫，在滴頭溫度為300℃，滴製振動頻率為300Hz、滴製壓力為4.0Bar的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-150℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥、包衣步驟：將冷卻後的固態滴丸進行流化乾燥及載藥包衣，乾燥溫度為150℃，製成粒徑為4.0mm的包衣微滴丸；(5)包裝步驟：將所述包衣微滴丸進行膠囊裝填，並通過膠囊檢重機完成100%線上檢重，然後包裝成最終產品。 (1) Chemical step: first add PEG-6000 to the chemical tank, heat to 120 ° C, pre-melt, then add traditional Chinese medicine composition, put into homogenizer, mix homogeneously at 5000 rpm, time 200 min, then homogenize at 10000 rpm Chemical material, time 1min, in the process of chemical material, the temperature of the material is kept at 100 ° C, to obtain molten liquid; (2) Drip step: the above molten liquid is transported to the dripper by pressurization, and the dripper is steamed The jacket is insulated, and the molten liquid is poured into the dripper and dripped from the bottom of the dripper under the condition that the dripper temperature is 300 ° C, the vibration frequency is 300 Hz, and the dropping pressure is 4.0 Bar; (3) Condensation step: the dripping drug drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is -150 ° C, so that the dripped liquid is cooled into a solid drop pill; (4) drying, coating step: after cooling The solid drop pellet is subjected to fluidized drying and drug-loading coating, and the drying temperature is 150 ° C to prepare a coated micro-droplet pellet having a particle diameter of 4.0 mm; (5) packaging step: capsule-filling the coated micro-droplet pellet And complete the 100% online checkweighing through the capsule checkweigher, and then package it into the final Products.

實施例29 Example 29

取實施例1製得的中藥組合物600g、冰片5g以及PEG-4000滴丸基質2400g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 2400 g of a PEG-4000 dropping base were used.

(1)化料步驟：先將PEG-4000加入化料罐中，加熱至120℃，預先熔融，再加入中藥組合物，以3000rpm均質混合，時間10min，然後，以4000rpm均質化料，時間5min，在化料過程中，物料的溫度保持在70~90℃，得熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭， 滴頭採用蒸汽夾套保溫，在滴頭溫度為70℃，滴製振動頻率為90Hz、滴製壓力為1.0Bar的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-140℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥步驟：將冷卻後的固態滴丸進行流化乾燥，乾燥溫度為150℃，製成粒徑為1.0mm的微滴丸素丸。 (1) Chemical step: first add PEG-4000 to the chemical tank, heat to 120 ° C, pre-melt, then add Chinese medicine composition, homogenize and mix at 3000 rpm for 10 min, then homogenize the material at 4000 rpm for 5 min. In the process of chemical compounding, the temperature of the material is maintained at 70-90 ° C to obtain a molten chemical solution; (2) the dropping step: the molten liquid solution is delivered to the dripper by pressurization. The dripper is insulated by a steam jacket, and the molten liquid is poured into the dripper and dripped from the bottom of the dripper under the condition that the dripper temperature is 70 ° C, the vibration frequency is 90 Hz, and the dropping pressure is 1.0 Bar. (3) Condensation step: the dripping drug drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is -140 ° C, so that the dripped liquid is cooled into a solid drop pill; (4) drying step: after cooling The solid pellet was subjected to fluidized drying, and the drying temperature was 150 ° C to prepare a micropellet pellet having a particle diameter of 1.0 mm.

實施例30 Example 30

取實施例1製得的中藥組合物600g、冰片5g以及PEG-4000滴丸基質2400g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 2400 g of a PEG-4000 dropping base were used.

(1)化料步驟：先將PEG-4000加入化料罐中，加熱至120℃，預先熔融，再加入中藥組合物，以4000rpm均質混合，時間60min，然後，以9000rpm均質化料，時間30min，在化料過程中，物料的溫度保持在90℃，得熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭，滴頭採用蒸汽夾套保溫，在滴頭溫度為100℃，滴製振動頻率為200Hz、滴製壓力為3.0Bar的條件下，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-140℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥步驟：將冷卻後的固態滴丸進行流化乾燥，乾燥溫度為150℃，製成粒徑為2.0mm的微滴丸素丸。 (1) Chemical step: firstly add PEG-4000 to the chemical tank, heat to 120 ° C, pre-melt, then add the traditional Chinese medicine composition, homogenize and mix at 4000 rpm for 60 min, then homogenize the material at 9000 rpm for 30 min. In the process of chemical material, the temperature of the material is maintained at 90 ° C to obtain a molten chemical solution; (2) the dropping step: the molten liquid is transported to the dripper by means of pressure, and the dripper is insulated by a steam jacket. The dripper temperature is 100 ° C, the dropping vibration frequency is 200 Hz, and the dropping pressure is 3.0 Bar, the molten chemical is poured into the dripper and dripped from the bottom of the dripper; (3) the condensation step: dripping The medicine drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is -140 ° C, so that the dripped liquid is cooled into a solid dropping pill; (4) drying step: the cooled solid dropping pills are fluidized and dried, The drying temperature was 150 ° C, and a micropellet pellet having a particle diameter of 2.0 mm was prepared.

實施例31 Example 31

取實施例1製得的中藥組合物600g、冰片5g以及PEG-6000滴丸基質2000g。 600 g of the traditional Chinese medicine composition prepared in Example 1, 5 g of borneol, and 2000 g of a PEG-6000 dropping base were taken.

(1)化料步驟：先將PEG-6000加入化料罐中，加熱至90℃，預先熔融，再加入中藥組合物，混合均勻成熔融藥液；(2)滴製步驟：將上述熔融藥液通過加壓方式輸送到滴頭， 滴頭採用蒸汽夾套保溫，在滴頭溫度為80℃，滴製振動頻率為50Hz，使所述熔融藥液流入滴頭，並從滴頭底部滴出；(3)冷凝步驟：滴出的藥滴在冷卻管道內採用低溫惰性氣體進行冷卻，冷卻溫度-20℃，使滴出的藥液冷卻成固態滴丸；(4)乾燥、包衣步驟：將冷卻後的固態滴丸進行流化乾燥及載藥包衣，乾燥溫度為75℃，製成粒徑為1.0~2.0mm的包衣微滴丸；(5)包裝步驟：將所述包衣微滴丸進行膠囊裝填，並通過膠囊檢重機完成100%線上檢重，然後包裝成最終產品。 (1) Chemical step: first add PEG-6000 to the chemical tank, heat to 90 ° C, pre-melt, then add the traditional Chinese medicine composition, mix and evenly into a molten liquid; (2) Drip step: the above molten medicine The liquid is delivered to the dripper by pressurization. The dripper is insulated by a steam jacket, the temperature of the dripper is 80 ° C, the vibration frequency is 50 Hz, the molten liquid is poured into the dripper, and dripped from the bottom of the dripper; (3) the condensation step: dripping The medicine drops are cooled in a cooling pipe by a low-temperature inert gas, and the cooling temperature is -20 ° C, so that the dripped liquid is cooled into a solid dropping pill; (4) drying, coating step: fluidizing the cooled solid dropping pills Drying and drug-loading coating, drying temperature is 75 ° C, making coated micro-droplets with particle diameter of 1.0-2.0 mm; (5) Packaging step: capsule-filling the coated micro-dropping pills, and passing the capsule The checkweigher completes 100% on-line checkweighing and then packages it into the final product.

其中，在滴製過程中，滴丸成形情況通過頻閃照射加目測，可進行即時線上監控及調整；在載藥包衣後，為提高滴丸的粒徑均勻度及圓整度，還可加入篩丸整粒步驟。 Among them, in the process of dropping, the forming of the dropping pills can be monitored and adjusted on the spot by stroboscopic irradiation and visual inspection; after the drug-loading coating, in order to improve the uniformity and roundness of the particle diameter of the dropping pills, Add the sieve pelleting step.

經過發明人的研究發現，比現有複方丹參滴丸產品而言，實施例15-31得到的微滴丸同樣具有療效好、生物利用度高、患者服用藥物劑量小、依從性好等類似的有益效果。 According to the research of the inventors, compared with the existing compound Danshen dropping pills product, the microdroplets obtained in Examples 15-31 also have similar effects, such as good curative effect, high bioavailability, small dosage of patients, good compliance, and the like. effect.

本發明丹酚酸T及其製劑的製備 Preparation of salvianolic acid T of the invention and preparation thereof

實施例32 Example 32

取丹參飲片，置中藥煎煮器中，加入丹參飲片品質6倍量的0.3%(w/v)的碳酸氫鈉水溶液，煎煮2.5h，濾過；濾液濃縮至相對密度1.22(80℃)的水提浸膏。 Take Danshen decoction pieces, place them in the Chinese medicine decoction device, add 0.3 times (w/v) sodium bicarbonate solution with the quality of Danshen Decoction pieces, boil for 2.5h, filter; the filtrate is concentrated to a relative density of 1.22 (80 °C). Water extracting extract.

在上述浸膏中加入95%(v/v)乙醇進行醇沉至醇含量60%(v/v)(25℃)，靜置24h；取上清液減壓濃縮至相對密度1.32(60℃)的醇沉浸膏。 95% (v/v) ethanol was added to the above extract to carry out alcohol precipitation to an alcohol content of 60% (v/v) (25 ° C), and allowed to stand for 24 hours; the supernatant was concentrated under reduced pressure to a relative density of 1.32 (60 ° C). Alcoholic immersion cream.

將上述醇沉浸膏用水溶解，過AB-8大孔吸附樹脂，用pH=3.0的鹽酸水溶液沖洗至洗脫液近乎無色，然後，用柱體積5倍量的95%(v/v)乙醇進行洗脫，洗脫液濃縮為無醇味的浸膏。 The above alcohol-sinking extract was dissolved in water, passed through an AB-8 macroporous adsorption resin, and washed with an aqueous solution of hydrochloric acid of pH=3.0 until the eluate was almost colorless, and then, with a column volume of 5 times the amount of 95% (v/v) ethanol. Elution, the eluate is concentrated to an alcohol-free extract.

將前一步驟得到的浸膏用流動相溶解(乙腈：水：甲酸(體積比)=15：85：1)，使用法國NOVASEP LC80-600動態軸向高壓 製備液相色譜儀進行純化，色譜填料為C18反相矽膠柱(10μm，YMC公司)；用乙腈：水：甲酸(體積比)=15：85：1進行等度洗脫；流速300mL/min；檢測波長280nm。使用高效液相色譜法監測洗脫過程，收集保留時間在21.2-24.0min的組分，用旋轉蒸發儀濃縮至幹，得到丹酚酸T樣品。 The extract obtained in the previous step was dissolved in the mobile phase (acetonitrile:water:formic acid (volume ratio)=15:85:1), using French NOVASEP LC80-600 dynamic axial high pressure Prepared by preparative liquid chromatography for purification, the chromatographic packing was C18 reverse phase tannin column (10 μm, YMC); isocratic elution with acetonitrile: water: formic acid (volume ratio) = 15:85:1; flow rate 300 mL / min; The detection wavelength was 280 nm. The elution process was monitored by high performance liquid chromatography, and the fractions with retention times of 21.2-24.0 min were collected and concentrated to dryness using a rotary evaporator to obtain a sample of salvianolic acid T.

將上述丹酚酸T樣品用流動相(乙腈：水：甲酸(體積比)=17：83：1)溶解，使用Waters Prep 400製備液相色譜儀進行手性異構體分離，色譜柱為CHIRALCEL® OD-RH反相手性色譜柱(250×20mm，5μm)；用乙腈：水：甲酸(體積比)=17：83：1進行等度洗脫；流速25mL/min；檢測波長280nm。使用高效液相色譜法監測洗脫過程，收集保留時間在19.5-21.1min的(S)-丹酚酸T組分、23.9-25.3min的(R)-丹酚酸T組分，先用旋轉蒸發儀在30℃下濃縮洗脫液，然後再凍幹，得到(S)-丹酚酸T和(R)-丹酚酸T純品。 The above sample of salvianolic acid T was dissolved in a mobile phase (acetonitrile:water:formic acid (volume ratio)=17:83:1), and a chiral isomer was separated using a Waters Prep 400 preparative liquid chromatograph. The column was CHIRALCEL. ® OD-RH reverse chiral column (250 x 20 mm, 5 μm); isocratic elution with acetonitrile:water: formic acid (volume ratio) = 17:83:1; flow rate 25 mL/min; detection wavelength 280 nm. The elution process was monitored by high performance liquid chromatography, and the (S)-salvianolic acid T component with a retention time of 19.5-21.1 min and the (R)-salvianolic acid T component of 23.9-25.3 min were collected and rotated first. The eluate was concentrated at 30 ° C and then lyophilized to obtain (S)-salvianolic acid T and (R)-salvian acid T pure product.

高分辨質譜給出准分子離子峰[M-H]-(S)-丹酚酸T m/z=537.1033；(R)-丹酚酸T m/z=537.1032。 High resolution mass spectrometry gave the excimer ion peak [M-H]-(S)-salvianolic acid Tm/z=537.1033; (R)-salvianolic acid Tm/z=537.1032.

(S)-丹酚酸T和(R)-丹酚酸T的核磁共振圖譜數據歸屬見下表： The NMR data of (S)-salvianolic acid T and (R)-salvianolic acid T are shown in the following table:

為了更好的證明本發明的有益效果，通過下述試驗來說明。 In order to better demonstrate the beneficial effects of the present invention, it is illustrated by the following test.

試驗實施例1 Test Example 1

1實驗材料 1 experimental material

動物 animal

SD大鼠，雄性，體重200g，北京維通利華實驗動物技術有限 公司，動物合格證號：SCXK(京)2007-0001。 SD rat, male, weighing 200g, Beijing Weitong Lihua experimental animal technology limited Company, animal certificate number: SCXK (Beijing) 2007-0001.

家兔，體重1.7-2.0kg，雄性，由南京江甯縣湯山青龍山動物繁殖場提供，實驗動物生產許可證：SCXK(蘇)2007-2008，實驗動物使用許可證：SCXK(蘇)2007-2008。 Rabbit, weight 1.7-2.0kg, male, provided by Tangshan Qinglongshan Animal Breeding Farm, Jiangning County, Nanjing, Laboratory Animal Production License: SCXK (Su) 2007-2008, Laboratory Animal Use License: SCXK (Su) 2007-2008 .

1.2藥物與試劑 1.2 drugs and reagents

按照實施例1製備：丹參三七提取物2種。提取物A(加冰片)、提取物B(無冰片)。水合氯醛，氯化三苯基四氮唑(TTC)。 Prepared according to Example 1: two kinds of extracts of Salvia miltiorrhiza. Extract A (with borneol), extract B (without borneol). Chloral hydrate, triphenyltetrazolium chloride (TTC).

阿司匹林腸溶片：南京白敬宇製藥有限責任公司，批號：111001。 Aspirin enteric-coated tablets: Nanjing Baijingyu Pharmaceutical Co., Ltd., batch number: 111001.

AA(花生四烯酸)：規格10mg/瓶，sigma公司提供，批號1001126252。 AA (arachidonic acid): Specification 10 mg/bottle, supplied by sigma, batch number 1001126252.

ADP(腺嘌呤核苷二磷酸單鈉鹽)：上海伯奧生物科技有限公司(進口分裝)，批號：990527；膠原：規格10mg/瓶，sigma公司提供，批號1001162038 ADP (adenine nucleoside diphosphate monosodium salt): Shanghai Boao Biotechnology Co., Ltd. (imported packaging), batch number: 990527; collagen: size 10mg / bottle, provided by sigma company, batch number 1001162038

2.實驗方法 2. Experimental methods

2.1大鼠急性心肌梗死實驗 2.1 Rat acute myocardial infarction experiment

32隻動物按體重隨機分為正常組，模型組、提取物A組(加冰片)、提取物B組(無冰片)，每組8隻。 Thirty-two animals were randomly divided into normal group by weight, model group, extract group A (with borneol), and extract group B (without borneol), with 8 rats in each group.

動物分組後，灌胃給藥1周，見表8。第8天，動物以10%水合氯醛(3ml/kg)腹腔內麻醉。麻醉後仰臥位固定於鼠板上，將導線***大鼠右前肢和雙後肢皮下，接MedLab-U/8c生物信號採集處理系統記錄大鼠II導心電圖。左胸前壁剃毛，經口腔氣管插管，接動物呼吸機，呼吸頻率80次/min，潮氣量3ml/100g，吸呼比1：1。胸部以左前外側切口剪斷第三肋進胸，用鑷子小心提起心包膜並撕開，大部分動物在左心耳下緣與肺動脈圓錐間可以看見左冠狀靜脈主幹走行，LAD與之伴行。用4-0醫用縫合絲線在距左心耳下緣約1-2mm處，左冠狀靜脈主幹附近的室間溝內，將LAD連同少量心肌組織一起縫紮。然後逐層關胸，待大鼠自主 呼吸恢復後拔除氣管插管。 After the animals were grouped, they were intragastrically administered for 1 week, as shown in Table 8. On day 8, animals were anesthetized intraperitoneally with 10% chloral hydrate (3 ml/kg). After anesthesia, the supine position was fixed on the rat plate, and the wire was inserted into the right forelimb and the hind limb of the rat. The rat II electrocardiogram was recorded by the MedLab-U/8c biosignal acquisition and processing system. The left chest wall was shaved, intubated through the oral trachea, and connected to the animal ventilator, respiratory rate 80 times / min, tidal volume 3ml / 100g, suction ratio 1:1. The left anterior lateral incision was used to cut the third rib into the chest. The pericardium was carefully lifted with tweezers and torn open. Most animals saw the left coronary vein trunk between the lower left atrial appendage and the pulmonary artery cone, and LAD was accompanied by it. The LAD was sutured together with a small amount of myocardial tissue with a 4-0 medical suture thread about 1-2 mm from the lower edge of the left atrial appendage, in the interventricular sulcus near the left coronary vein trunk. Then close the chest layer by layer, wait for the rats to autonomously Remove the tracheal intubation after breathing recovery.

檢測指標設定：結紮4小時後，動物處死，將心臟取下，0.9%氯化鈉注射液沖洗吸去水分，沿冠狀溝剪去心房稱心室濕品質。沿心室溝從心尖到心基部平行將心室切成1mm厚的心肌片(5片)，將心肌置於TTC染色劑中，在37℃恒溫水浴中染色15min，正常心肌被染為紅色，梗死區心肌為白色，精密稱取每片心肌梗死區濕品質，然後計算梗死區濕重量占心室濕品質的百分率(%)判斷梗死範圍。 Detection index setting: After 4 hours of ligation, the animals were sacrificed, the heart was removed, 0.9% sodium chloride injection was washed to remove water, and the atrial sac was weighed along the coronary sulcus. The ventricle was cut into 1 mm thick myocardial slices (5 pieces) from the apex to the base of the heart along the ventricular sulcus. The myocardium was placed in the TTC stain, stained for 15 min in a constant temperature water bath at 37 ° C, and the normal myocardium was stained red. The myocardium was white, and the wet quality of each myocardial infarction area was accurately weighed. Then the percentage of wet weight in the infarct area (%) was calculated to determine the infarct size.

2.2家兔血小板聚集率實驗 2.2 rabbit platelet aggregation rate experiment

家兔隨機分為4組：模型對照組給予蒸餾水、阿司匹林60mg/ml組，提取物A低、高劑量組給藥劑量為42、84mg/kg(分別為臨床等效劑量的1、2倍)；灌胃給藥，每日1次，連續7天。給藥容積為1ml/kg體重。於第7天灌胃給藥後60min局麻下頸動脈放血，枸櫞酸鈉(3.8%)1：9抗凝，以1000r/min離心10min，取富血小板血漿(PRP)，剩餘部分以3000r/min離心，取貧血小板血漿(PPP)，聚集誘導劑用ADP(終濃度3μg/ml)，AA(終濃度80μg/ml)，膠原(5μg/ml)。用STEELIEX血小板聚集及凝血因數分析儀測定血小板max聚集率，並按下述公式計算抑制率。 Rabbits were randomly divided into 4 groups: model control group was given distilled water and aspirin 60 mg/ml group, and extract A low and high dose group was administered at doses of 42, 84 mg/kg (1 and 2 times of clinical equivalent dose, respectively). Oral administration, once a day for 7 consecutive days. The administration volume was 1 ml/kg body weight. On the 7th day, 60 minutes after intragastric administration, the carotid artery was exsanguinated under local anesthesia. Sodium citrate (3.8%) was anticoagulated 1:9, centrifuged at 1000r/min for 10 minutes, and platelet-rich plasma (PRP) was taken. The remaining part was 3000r. Centrifugation at /min, platelet-poor plasma (PPP), aggregation inducer with ADP (final concentration 3 μg/ml), AA (final concentration 80 μg/ml), collagen (5 μg/ml). The platelet max aggregation rate was measured using a STEELIEX platelet aggregation and coagulation factor analyzer, and the inhibition rate was calculated according to the following formula.

3.實驗結果 3. Experimental results

3.1大鼠心肌梗塞實驗結果 3.1 Rat myocardial infarction test results

結果見表9，在預給藥7天後，提取物A、B組，心肌梗死部分重量(0.0685±0.0182，0.0923±0.0191)與模型組(0.1209±0.0199g)比較明顯減少，且有統計學意義。根據組間比較資料，A組的心梗比例相較B組有顯著的降低，且兩組間資料存在顯著性差異(p<0.05)。 The results are shown in Table 9. After 7 days of pre-administration, the weights of myocardial infarction (0.0685±0.0182, 0.0923±0.0191) and the model group (0.1209±0.0199g) were significantly reduced in the extracts A and B, and there were statistics. significance. According to the comparison data between groups, the proportion of myocardial infarction in group A was significantly lower than that in group B, and there was significant difference between the two groups (p<0.05).

注：和模型組相比，*：p<0.05；和A組相比，#：p<0.05 Note: Compared with the model group, *:p<0.05; compared with group A, # :p<0.05

3.2對家兔血小板聚集率的影響結果 3.2 Results of platelet aggregation rate in rabbits

由表10可見，提取物A對ADP誘導的家兔血小板聚集率、有抑制作用，與空白組比較差異有顯著性。提取物A抑制ADP誘導的血小板聚集作用和阿斯匹林無顯著性差異。 It can be seen from Table 10 that extract A has an inhibitory effect on ADP-induced platelet aggregation rate in rabbits, and is significantly different from the blank group. Extract A inhibited ADP-induced platelet aggregation and no significant difference in aspirin.

*P<0.05 ** P<0.01，與空白組比較。 *P<0.05 **P<0.01, compared with the blank group.

由表11可見，提取物A對AA誘導的家兔血小板聚集率、有抑制作用，與空白組比較差異有顯著性。提取物A抑制AA誘導的血小板聚集作用和阿斯匹林無顯著性差異。 It can be seen from Table 11 that extract A has an inhibitory effect on AA-induced platelet aggregation rate in rabbits, and is significantly different from the blank group. Extract A inhibited AA-induced platelet aggregation and no significant difference in aspirin.

*P<0.05 ** P<0.01，與模型對照組比較。 *P<0.05 **P<0.01, compared with the model control group.

由表12可見，提取物A對膠原誘導的家兔血小板聚集率、有抑制作用，與空白組比較差異有顯著性。提取物A抑制膠原誘導的血小板聚集作用和阿斯匹林無顯著性差異。 As can be seen from Table 12, extract A had an inhibitory effect on collagen-induced platelet aggregation rate in rabbits, and was significantly different from the blank group. Extract A inhibited collagen-induced platelet aggregation and no significant difference in aspirin.

*P<0.05 ** P<0.01，與模型對照組比較。 *P<0.05 **P<0.01, compared with the model control group.

4.討論 4. Discussion

根據本實驗結果，僅用丹參三七提取物(B組)，連續給予7 天，即可起到抗大鼠結紮性心肌梗塞的藥效作用。 According to the results of this experiment, only the extract of Salvia miltiorrhiza Bge. (Group B) was given continuously for 7 In days, it can play a pharmacological effect against rat ligation of myocardial infarction.

丹參三七提取物加上冰片(A組)連續給予7天，該組動物的心梗率明顯小於不含冰片的B組。而且對ADP、AA、膠原誘導的家兔血小板聚集率均有顯著抑制作用。 Danshen notoginseng extract plus borneol (group A) was given for 7 consecutive days. The myocardial infarction rate of this group of animals was significantly lower than that of group B without borneol. Moreover, the platelet aggregation rate of rabbits induced by ADP, AA and collagen was significantly inhibited.

初步結論為在抗心肌梗塞的藥效中，增加冰片具有一定加強藥效作用。 The preliminary conclusion is that in the efficacy of anti-myocardial infarction, the addition of borneol has a certain potentiating effect.

試驗實施例2：兩種複方丹參滴丸樣品對大鼠急性心肌梗死影響的比較試驗 Test Example 2: Comparative experiment of two kinds of compound Danshen dripping pills samples on acute myocardial infarction in rats

1.實驗動物：SD大鼠，雄性，體重340~360g，購自北京維通利華實驗動物技術有限公司，動物合格證號：SCXK(京)2007-0001。 1. Experimental animals: SD rats, male, weighing 340-360 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., animal certificate number: SCXK (Beijing) 2007-0001.

2.藥物、試劑和儀器：本發明的複方丹參微滴丸按照複方丹參微滴丸製備例15進行製備。 2. Drugs, reagents and instruments: The compound Danshen micro-drop pellets of the present invention were prepared in accordance with Preparation Example 15 of Compound Danshen Micro-droplets.

對比藥物：國內已經上市的複方丹參滴丸，天津天士力製藥股份有限公司。 Comparative drugs: Compound Danshen Dripping Pills, Tianjin Tianshili Pharmaceutical Co., Ltd., which has been listed in China.

麻醉用水合氯醛、氯化三苯基四氮唑(TTC)。 Anesthesia with chloral hydrate, triphenyltetrazolium chloride (TTC).

實驗儀器：MedLab-U/8c生物信號採集處理系統，南京美易公司。 Experimental instrument: MedLab-U/8c biological signal acquisition and processing system, Nanjing Meiyi Company.

3.實驗方法 3. Experimental methods

動物分組：將試驗大鼠按照體重隨機分為S組(假手術組)、M組(模型組)、Y組(陽性藥組，酒石酸美托洛爾，批號：1201039)、F組(本發明的複方丹參微滴丸)、G組(國內產品，批號：2011L16)，每組10隻。 Animal grouping: The test rats were randomly divided into S group (sham operation group), M group (model group), Y group (positive drug group, metoprolol tartrate, lot number: 1201039) and F group according to body weight (present invention) Compound Danshen micro-drop pills), Group G (domestic products, batch number: 2011L16), 10 in each group.

造模及給藥方法：動物分組後，灌胃給藥7d，見表13。第8d，大鼠以10%水合氯醛(3ml/kg)腹腔內麻醉。麻醉後仰臥位固定於小木板上，以大頭針***大鼠右前肢和雙後肢皮下，連接MedLab-U/8c生物信號採集處理系統，記錄大鼠心電圖。左胸前 壁剃毛，經口腔氣管插管，連接動物呼吸機，呼吸頻率80次/min，潮氣量3ml/100g，吸呼比1：1。胸部以左前外側切口剪斷第三肋進胸，用鑷子小心提起心包膜並撕開，大部分動物在左心耳下緣與肺動脈圓錐間可以看見左冠狀靜脈主幹走行，LAD與之伴行。 用4-0醫用縫合絲線在距左心耳下緣約1~2mm處，左冠狀靜脈主幹附近的室間溝內，將LAD連同少量心肌組織一起縫紮。觀察見心電圖有J點升高0.1mV以及左心室前壁變蒼白者表示模型建立成功。然後逐層關胸，待大鼠自主呼吸恢復後拔除氣管插管。連續記錄心電圖4h，動物麻醉狀態下剪取心臟，切片染色，計算心肌梗死率；取動物血清，備用。 Modeling and administration methods: After the animals were grouped, they were intragastrically administered for 7 days, as shown in Table 13. On day 8d, rats were anesthetized intraperitoneally with 10% chloral hydrate (3 ml/kg). After anesthesia, the supine position was fixed on a small wooden board, and the needle was inserted into the right forelimb and the lower hind limb of the rat, and the MedLab-U/8c biosignal acquisition and treatment system was connected to record the electrocardiogram of the rat. Left chest The wall was shaved, intubated through the oral trachea, connected to the animal ventilator, respiratory rate 80 times / min, tidal volume 3ml / 100g, suction ratio 1:1. The left anterior lateral incision was used to cut the third rib into the chest. The pericardium was carefully lifted with tweezers and torn open. Most animals saw the left coronary vein trunk between the lower left atrial appendage and the pulmonary artery cone, and LAD was accompanied by it. The LAD was sutured together with a small amount of myocardial tissue with a 4-0 medical suture thread at a distance of about 1 to 2 mm from the lower edge of the left atrial appendage and in the interventricular sulcus near the left main coronary vein. Observed that the electrocardiogram had a J point increase of 0.1 mV and the left ventricular anterior wall became pale, indicating that the model was successfully established. Then the chest was closed layer by layer, and the tracheal intubation was removed after the rat's spontaneous breathing resumed. The electrocardiogram was continuously recorded for 4 h, the heart was cut under anesthesia, and the sections were stained to calculate the myocardial infarction rate; the animal serum was taken and used.

心肌梗死率(%)=梗死區濕重/全心濕重×100% Myocardial infarction rate (%) = infarct wet weight / whole heart wet weight × 100%

4.實驗結果 4. Experimental results

4.1對心肌梗死率的影響 4.1 Impact on myocardial infarction rate

結果見表14。由表14可見，在預給藥7天後，M組(模型組)心肌梗死率顯著高於S組(假手術組)，說明模型成功。G組、F組的心肌梗死率分別為3.38%、3.32%，顯著低於模型組(5.07%)，且有顯著性差異(p<0.01)，說明兩樣品均具有一定的抗急性心肌梗死作用。但是，G組和F組相比，心肌梗死率無統計學上的差異(p>0.05)。 The results are shown in Table 14. As can be seen from Table 14, the myocardial infarction rate of the M group (model group) was significantly higher than that of the S group (sham operation group) after 7 days of pre-administration, indicating that the model was successful. The myocardial infarction rates of group G and group F were 3.38% and 3.32%, respectively, which were significantly lower than that of the model group (5.07%), and there was a significant difference (p<0.01), indicating that both samples have certain anti-acute myocardial infarction. . However, there was no statistically significant difference in myocardial infarction rate between the G group and the F group (p>0.05).

注：與M組(模型組)相比，*：p<0.01；與Y組(陽性藥組)相比，#：p<0.01 Note: Compared with group M (model group), *:p<0.01; compared with group Y (positive group), #:p<0.01

4.2對心梗大鼠心率的影響 4.2 Effects on heart rate in rats with myocardial infarction

結果見表15，各組大鼠在觀測時間內，結紮0~1h內，各組大鼠心率大小依次為F組，G組、M組、Y組、S組，1h後，各組心率均出現下降趨勢。在觀察時間內，Y組、S組的心率變化較平穩。各組大鼠間心率無顯著性差異。 The results are shown in Table 15. During the observation period, the rats in each group were ligated for 0~1h. The heart rate of each group was F group, G group, M group, Y group, S group. After 1h, the heart rate of each group was There is a downward trend. During the observation time, the heart rate changes of group Y and group S were relatively stable. There was no significant difference in heart rate between the groups.

5.結論：在本實驗設定的劑量下，各組對冠狀動脈結紮大鼠均具有一定的抗急性心肌梗死作用，尤其是本發明的微滴丸在劑量84mg/kg時的心肌梗死率3.38±0.49%與國內的複方丹參滴丸產品在劑量115mg/kg的心肌梗死率3.32±0.59%的療效相似。由此可見，本發明的微滴丸在劑量84mg/kg就能達到國內複方丹參滴丸產品在劑量115mg/kg的藥效作用，其療效優於現有複方丹參滴丸，且具有生物利用度高、患者服用藥物劑量小、依從性好等有益效果。 5. Conclusions: At the doses set in this experiment, each group had certain anti-acute myocardial infarction effects on coronary artery ligation rats, especially the myocardial infarction rate of the micro-drop pills of the present invention at the dose of 84 mg/kg was 3.38± 0.49% was similar to the domestic compound Danshen dripping pill product at a dose of 115 mg/kg of myocardial infarction rate of 3.32±0.59%. It can be seen that the micro-droplet of the present invention can achieve the pharmacodynamic effect of the domestic compound Danshen dripping pill product at a dose of 115 mg/kg at a dose of 84 mg/kg, and the curative effect is superior to the existing compound Danshen dripping pill, and has high bioavailability. The patient takes a small dose of medication and has good beneficial effects.

Claims (22)

一種中藥組合物，所述中藥組合物是由以重量百分比計的丹參三七提取物50.0%~99.9%和冰片0.1%~50.0%組成的，其中，所述丹參三七提取物含有以下組分，各組分的重量比為：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(2~6)：(0.5~2)：(1~3)：(0.2~1)：(0.2~1)：(0.5~2)：(0.5~2)：(0.2~1)：(1~4)：(0.1~0.5)：(1~4)：(0.1~1)：(0.01~0.05)：(0.05~0.1)：(0.02~0.1)：(0.1~0.5)。 A traditional Chinese medicine composition consisting of 50.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 50.0% of borneol in weight percentage, wherein the extract of Salvia miltiorrhiza Bge. contains the following components The weight ratio of each component is: Danshensu: salvianolic acid T: protocatechuic aldehyde: salvianolic acid D: rosmarinic acid: salvianolic acid B: salvianolic acid A: notoginsenoside R1: ginsenoside Rg1 : ginsenoside Re: ginsenoside Rb1: ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = (2~6): (0.5~2): (1~3): (0.2~1) :(0.2~1):(0.5~2):(0.5~2):(0.2~1):(1~4):(0.1~0.5):(1~4):(0.1~1):( 0.01~0.05): (0.05~0.1): (0.02~0.1): (0.1~0.5). 如請求項1所述的中藥組合物，其中，所述中藥組合物是由以重量百分比計的丹參三七提取物75.0%~99.9%和冰片0.1%~25.0%組成的。 The traditional Chinese medicine composition according to claim 1, wherein the traditional Chinese medicine composition is composed of 75.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 25.0% of borneol. 如請求項1所述的中藥組合物，其中，所述中藥組合物是由以重量百分比計的丹參三七提取物90.0%~99.9%和冰片0.1%~10.0%組成的。 The traditional Chinese medicine composition according to claim 1, wherein the traditional Chinese medicine composition is composed of a weight percentage of 90.0% to 99.9% of Salvia miltiorrhiza extract and 0.1% to 10.0% of borneol. 如請求項1至3中任一項所述的中藥組合物，其中，所述丹參三七提取物含有以下組分，各組分的重量比為：丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A：三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=(3~4)：(0.9~1.2)：(1.4~2.0)：(0.5~0.7)：(0.5~0.9)：(1~1.6)：(0.7~1.2)：(0.5~0.9)：(1.8~2.8)：(0.2~0.4)：(1.7~2.2)：(0.2~0.6)：(0.03~0.04)：(0.07~0.08)：(0.05~0.06)：(0.26~0.28)。 The traditional Chinese medicine composition according to any one of claims 1 to 3, wherein the extract of Salvia miltiorrhiza Bge. contains the following components, and the weight ratio of each component is: Danshensu: salvianolic acid T: protocatechu Aldehyde: Salvianolic acid D: Rosmarinic acid: Salvianolic acid B: Salvianolic acid A: Notoginsenoside R1: Ginsenoside Rg1: Ginsenoside Re: Ginsenoside Rb1: Ginsenoside Rd: Dihydrotansinone I: Tanshinone I : cryptotanshinone: tanshinone IIA=(3~4): (0.9~1.2): (1.4~2.0): (0.5~0.7): (0.5~0.9): (1~1.6): (0.7~1.2):( 0.5~0.9):(1.8~2.8):(0.2~0.4):(1.7~2.2):(0.2~0.6):(0.03~0.04):(0.07~0.08):(0.05~0.06):(0.26~ 0.28). 如請求項4所述的中藥組合物，其中，所述丹參三七提取物含有以下組分，各組分的重量比為： 丹參素：丹酚酸T：原兒茶醛：丹酚酸D：迷迭香酸：丹酚酸B：丹酚酸A；三七皂苷R1：人參皂苷Rg1：人參皂苷Re：人參皂苷Rb1：人參皂苷Rd：二氫丹參酮I：丹參酮I：隱丹參酮：丹參酮IIA=3.6：1.1：1.7：0.6：0.7：1.3：0.9：0.7：2.4：0.3：1.8：0.4：0.03：0.07：0.06：0.27。 The traditional Chinese medicine composition according to claim 4, wherein the extract of Salvia miltiorrhiza Bge. contains the following components, and the weight ratio of each component is: Danshensu: salvianolic acid T: protocatechuic aldehyde: salvianolic acid D: rosmarinic acid: salvianolic acid B: salvianolic acid A; notoginsenoside R1: ginsenoside Rg1: ginsenoside Re: ginsenoside Rb1: Ginsenoside Rd: dihydrotanshinone I: tanshinone I: cryptotanshinone: tanshinone IIA = 3.6: 1.1: 1.7: 0.6: 0.7: 1.3: 0.9: 0.7: 2.4: 0.3: 1.8: 0.4: 0.03: 0.07: 0.06: 0.27. 如請求項1至3中任一項所述的中藥組合物，其中，所述丹參三七提取物是由原材料按以下重量份製備得到的：丹參75~90份、三七10~25份。 The traditional Chinese medicine composition according to any one of claims 1 to 3, wherein the extract of Salvia miltiorrhiza Bge. is prepared from the raw materials in the following parts by weight: 75-90 parts of Salvia miltiorrhiza and 10-25 parts of Sanqi. 如請求項6所述的中藥組合物，其中，所述丹參三七提取物是由原材料按以下重量份製備得到的：丹參82~84份、三七16~17份。 The traditional Chinese medicine composition according to claim 6, wherein the extract of Salvia miltiorrhiza Bge. is prepared from the raw materials in the following parts by weight: 82-84 parts of Salvia miltiorrhiza and 16-17 parts of Sanqi. 一種藥物製劑，所述製劑包含如請求項1至7中任一項所述的中藥組合物及藥學上可接受的載體。 A pharmaceutical preparation comprising the traditional Chinese medicine composition according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier. 如請求項8所述的藥物製劑，其中，所述藥物製劑為滴丸劑或微滴丸劑，優選微滴丸劑，所述微滴丸劑是由中藥組合物與滴丸基質按照重量比1：5~5：1製成的。 The pharmaceutical preparation according to claim 8, wherein the pharmaceutical preparation is a pill or a micropellet, preferably a micropellet, and the micropill is a weight ratio of the Chinese medicine composition to the dropping matrix 1:5~ Made of 5:1. 一種複方丹參微滴丸劑，其中，所述複方丹參微滴丸是由重量比為1：5~5：1的中藥組合物與滴丸基質製成，所述中藥組合物是如請求項1至7中任一項所述的中藥組合物。 A compound Danshen micro-dropping pill, wherein the compound Danshen micro-dropping pill is made of a traditional Chinese medicine composition and a dropping pill base in a weight ratio of 1:5 to 5:1, the Chinese medicine composition is as claimed in claim 1 A traditional Chinese medicine composition according to any one of the preceding claims. 如請求項10所述的微滴丸劑的製備方法，其中，所述方法包括以下步驟：(1)化料步驟：將藥物與滴丸基質投入均質機中，以1000~5000rpm均質混合，時間為1~200min，然後，以3000~10000rpm均質化料，時間為1~100min，在化料過程中，溫度保持在60~100℃，得熔融藥液，所述藥物與所述滴丸基質的重量比為1：5~5：1；(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度為 70~300℃、滴製振動頻率為2~2000Hz、滴製壓力為0.5~4.0Bar、及加速度為1~20G的條件下，經滴頭振動滴製，滴製速度與上述步驟(1)化料速度匹配；以及(3)冷凝步驟：將滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm~4.0mm固態滴丸，所述冷卻氣體的溫度為0℃以下。 The method for preparing a micropump according to claim 10, wherein the method comprises the following steps: (1) a chemical step: the drug and the dropping pill matrix are put into a homogenizer, and homogeneously mixed at 1000 to 5000 rpm for a time of 1~200min, then homogenizing the material at 3000~10000rpm for 1~100min. During the chemical process, the temperature is maintained at 60~100°C, and the molten liquid is obtained, and the weight of the drug and the dropping matrix is obtained. The ratio is 1:5~5:1; (2) the dropping step: the above molten liquid is delivered to the dripper at the temperature of the dripper 70~300°C, the vibration frequency of the drop is 2~2000Hz, the dropping pressure is 0.5~4.0Bar, and the acceleration is 1~20G. The drip vibrating drops, the dropping speed and the above steps (1) The material speed is matched; and (3) the condensation step: the dripping drug droplet is rapidly cooled in a cooling gas, and solidified into a solid drop pellet having a particle diameter of 0.2 mm to 4.0 mm, and the temperature of the cooling gas is 0 ° C or lower. 如請求項11所述的製備方法，其中，上述步驟(1)中，所述滴丸基質包括PEG類、山梨醇、木糖醇、乳糖醇、麥芽糖、澱粉、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、***膠、海藻酸、糊精、環糊精、瓊脂、乳糖中的一種或多種組合；優選的滴丸基質為固體PEG，例如PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-5000、PEG-6000、PEG-7000、PEG-8000，進一步優選PEG-1000、PEG-2000、PEG-3000、PEG-4000、PEG-6000、PEG-8000中的一種或多種組合，最優選為PEG-6000、PEG-4000或PEG-4000和PEG-6000的組合。 The preparation method according to claim 11, wherein in the above step (1), the dropping matrix comprises PEG, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, carboxymethyl One or more combinations of sodium cellulose, hydroxypropyl methylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, lactose; preferred pellet base is solid PEG, such as PEG-1000, PEG -2000, PEG-3000, PEG-4000, PEG-5000, PEG-6000, PEG-7000, PEG-8000, further preferably PEG-1000, PEG-2000, PEG-3000, PEG-4000, PEG-6000, PEG One or more combinations of -8000, most preferably PEG-6000, PEG-4000 or a combination of PEG-4000 and PEG-6000. 如請求項11或12所述的製備方法，其中，所述方法包括以下步驟：(1)化料步驟：將藥物與滴丸基質投入均質機中，以1000~5000rpm均質混合，然後，以3000~10000rpm均質化料，時間為20~80min，在化料過程中，溫度保持在80~100℃，得熔融藥液，所述藥物與所述滴丸基質的重量比為1：3~3：1；(2)滴製步驟：將上述熔融藥液輸送至滴頭，在滴頭溫度為70~200℃、滴製振動頻率為20~300Hz、滴製壓力為0.5~4.0Bar、及加速度為1~15G的條件下，經滴頭振動滴製，滴製速度與上述步驟(1)化料速度匹配；以及(3)冷凝步驟：將滴出的藥滴在冷卻氣體中快速冷卻，凝固成粒徑為0.2mm~4.0mm固態滴丸，所述冷卻氣體的溫度為0℃以下。 The preparation method according to claim 11 or 12, wherein the method comprises the following steps: (1) a chemical step: feeding the drug and the dropping matrix into a homogenizer, mixing homogeneously at 1000 to 5000 rpm, and then, 3000 ~10000rpm homogenized material, the time is 20~80min, during the process of the chemical, the temperature is maintained at 80~100 °C, the molten liquid is obtained, and the weight ratio of the drug to the dropping matrix is 1:3~3: 1; (2) Drip step: the above molten liquid is transported to the dripper at a dripper temperature of 70-200 ° C, a drip vibration frequency of 20-300 Hz, a drip pressure of 0.5-4.0 Bar, and an acceleration of Under the condition of 1~15G, the dropping speed is matched with the speed of the above step (1) by the dripper; and (3) the condensation step: the dripping drug drops are rapidly cooled in the cooling gas, and solidified into The solid particle droppings having a particle diameter of 0.2 mm to 4.0 mm, and the temperature of the cooling gas is 0 ° C or lower. 如請求項12所述的製備方法，其中，上述步驟(1)中，所述藥物與所述滴丸基質的重量比為1：3~3：1，以3000~5000rpm均質混合，時間為10~60min，然後，以4000~9000rpm均質化料，時間為5~30min，在化料過程中，溫度保持在70~90℃；優選所述藥物與所述滴丸基質的重量比為1：(1~3)，以3000~4000rpm均質混合，時間10-30min，然後，以4000~6000rpm均質化料，時間6~30min，在化料過程中，溫度保持在75~85℃。 The preparation method according to claim 12, wherein in the above step (1), the weight ratio of the drug to the pill matrix is 1:3 to 3:1, and the mixture is homogeneously mixed at 3000 to 5000 rpm for 10 hours. ~60min, then, homogenize the material at 4000~9000rpm for 5~30min, during the process, the temperature is maintained at 70~90°C; preferably the weight ratio of the drug to the dropping matrix is 1: ( 1~3), homogenize and mix at 3000~4000rpm for 10-30min, then homogenize the material at 4000~6000rpm for 6~30min. During the chemical process, the temperature is maintained at 75~85°C. 如請求項12所述的製備方法，其中，上述步驟(2)中，滴頭溫度為70~100℃、優選75~85℃；滴製振動頻率為50~300Hz、優選100~200Hz、更優選90~200Hz、更優選130~140Hz、最優選137Hz；加速度為3.5~4.5G、優選4.0G；滴製壓力為1.0~3.0Bar、優選1.8Bar；滴製速度為10~40kg/h，優選12~30kg/h，進一步優選15~25kg/h。 The preparation method according to claim 12, wherein in the step (2), the dripper temperature is 70 to 100 ° C, preferably 75 to 85 ° C; the dropping vibration frequency is 50 to 300 Hz, preferably 100 to 200 Hz, more preferably 90~200Hz, more preferably 130~140Hz, most preferably 137Hz; acceleration is 3.5~4.5G, preferably 4.0G; the dropping pressure is 1.0~3.0Bar, preferably 1.8Bar; the dropping speed is 10~40kg/h, preferably 12 ~30 kg/h, further preferably 15 to 25 kg/h. 如請求項12所述的製備方法，其中，上述步驟(3)中，所述氣體為空氣、氮氣、或惰性氣體；冷卻溫度為0~-150℃、優選-60~-140℃、更優選-80~-120℃；所述滴丸的直徑為1.0mm~2.0mm。 The preparation method according to claim 12, wherein in the above step (3), the gas is air, nitrogen, or an inert gas; the cooling temperature is 0 to -150 ° C, preferably -60 to -140 ° C, more preferably -80~-120 ° C; the diameter of the dropping pills is 1.0 mm to 2.0 mm. 如請求項11至16中任一項所述的製備方法，其中，所述製備方法還包括步驟(4)的乾燥步驟，採用流化乾燥設備乾燥，在-20~100℃、優選-20~90℃乾燥1~4h，得素丸。 The preparation method according to any one of claims 11 to 16, wherein the preparation method further comprises the drying step of the step (4), which is dried by a fluidized drying apparatus at -20 to 100 ° C, preferably -20 Dry at 90 ° C for 1 ~ 4h, get the pill. 如請求項17所述的製備方法，其中，經所述步驟(3)完成滴製後的低溫滴丸，經過溫度40~150℃、優選溫度40~60℃的流化床乾燥，乾燥時間為1~4h、優選1~3h、最優選為2h，得素丸。 The preparation method according to claim 17, wherein the low-temperature dropping pills after the completion of the step (3) are dried by a fluidized bed having a temperature of 40 to 150 ° C and preferably a temperature of 40 to 60 ° C, and the drying time is 1~4h, preferably 1~3h, most preferably 2h, get the pill. 如請求項18所述的製備方法，其中，所述步驟(4)採用梯度升溫乾燥法：於-20~30℃形成流化態，於15~35℃乾燥10~120min，於35~55℃乾燥10~60min，於55~100℃乾燥0~60min；優選地，所述梯度升溫乾燥法如下進行：於0~20℃形成流化態，於25℃乾燥60min，於45℃乾燥30min，於55℃乾燥0~30min。 The preparation method according to claim 18, wherein the step (4) adopts a gradient heating method: forming a fluidized state at -20 to 30 ° C, and drying at 15 to 35 ° C for 10 to 120 minutes at 35 to 55 ° C. Drying for 10~60min, drying at 55~100°C for 0~60min; preferably, the gradient heating method is carried out as follows: forming a fluidized state at 0~20°C, drying at 25°C for 60min, drying at 45°C for 30min, Dry at 55 ° C for 0 ~ 30min. 如請求項11至19中任一項所述的製備方法，其中，所述製備方法還包括步驟(5)的包衣步驟，所述步驟(5)是在所述步驟(4)得到的素丸處於流化狀態下，在30~65℃溫度下對所述素丸進行包衣；包衣液濃度為5~25wt%，優選18~20wt%，其中，包衣材料選自：蟲膠、苯二甲酸醋酸纖維素、丙烯酸甲酯、甲基丙烯酸甲酯或歐巴代；所述包衣材料與所述素丸的重量比為1：50~1：10、優選1：50~1：25。 The production method according to any one of claims 11 to 19, wherein the preparation method further comprises a coating step of the step (5), wherein the step (5) is a pigment obtained in the step (4) The pellet is in a fluidized state, and the pellet is coated at a temperature of 30 to 65 ° C; the concentration of the coating liquid is 5 to 25 wt%, preferably 18 to 20 wt%, wherein the coating material is selected from the group consisting of: shellac, Cellulose acetate phthalate, methyl acrylate, methyl methacrylate or Opadry; the weight ratio of the coating material to the pellets is 1:50 to 1:10, preferably 1:50 to 1: 25. 如請求項11至20中任一項所述的製備方法，其中，所述製備方法在所述步驟(1)前，還可以具有物料預混步驟，將所述藥物浸膏或粉末加水後，於30~80℃攪拌10min以上，得到藥物預混料。 The preparation method according to any one of claims 11 to 20, wherein, before the step (1), the preparation method may further have a material pre-mixing step, after adding the drug extract or powder to water, Stir at 30~80 ° C for more than 10 min to obtain a drug premix. 一種如請求項1至7中任一項所述的中藥組合物在製備治療急性心肌梗塞和急性心肌缺血的藥物中的應用。 Use of a traditional Chinese medicine composition according to any one of claims 1 to 7 for the preparation of a medicament for the treatment of acute myocardial infarction and acute myocardial ischemia.
TW103124002A 2013-07-11 2014-07-11 Traditional Chinese medicine composition and use thereof, medicinal preparation containing the traditional Chinese medicine composition and compound salvia miltiorrhiza micropill, and preparation method of the microdrop pill TWI631956B (en)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
??201310290968.8 2013-07-11
CN201310290968 2013-07-11
??201310384234.6 2013-08-29
CN201310384234 2013-08-29
CN201410044675 2014-01-30
??201410044675.6 2014-01-30
??201410085152.6 2014-03-10
CN201410085152 2014-03-10

Publications (2)

Publication Number Publication Date
TW201536306A true TW201536306A (en) 2015-10-01
TWI631956B TWI631956B (en) 2018-08-11

Family

ID=52250181

Family Applications (1)

Application Number Title Priority Date Filing Date
TW103124002A TWI631956B (en) 2013-07-11 2014-07-11 Traditional Chinese medicine composition and use thereof, medicinal preparation containing the traditional Chinese medicine composition and compound salvia miltiorrhiza micropill, and preparation method of the microdrop pill

Country Status (17)

Country Link
US (2) USRE49035E1 (en)
EP (1) EP3020408B1 (en)
JP (2) JP6906307B2 (en)
KR (1) KR102189849B1 (en)
CN (1) CN104274520B (en)
AU (1) AU2014289763B2 (en)
CA (1) CA2916963C (en)
DK (1) DK3020408T3 (en)
EA (1) EA034217B1 (en)
ES (1) ES2905267T3 (en)
GE (1) GEP20186877B (en)
HK (1) HK1220908A1 (en)
HU (1) HUE058040T2 (en)
MX (1) MX2015017697A (en)
TW (1) TWI631956B (en)
UA (1) UA118968C2 (en)
WO (1) WO2015003659A1 (en)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015003662A1 (en) 2013-07-11 2015-01-15 天士力制药集团股份有限公司 Traditional chinese medicine composition, and preparation and application thereof
MX2015017651A (en) * 2013-07-11 2016-11-14 Tasly Pharmaceutical Group Co Preparation method for traditional chinese medicine micro drop pill and traditional chinese medicine micro drop pill prepared by using the method.
AU2014289763B2 (en) 2013-07-11 2019-03-07 Tasly Pharmaceutical Group Co., Ltd. Traditional chinese medicine composition, and preparation and application thereof
CN104418744B (en) 2013-08-29 2017-03-01 天士力制药集团股份有限公司 A kind of new salvianolic acid compound T, Preparation Method And The Use
CN104825335B (en) * 2015-05-12 2019-03-01 杭州杭睿科技有限公司 A kind of Chinese medicine process equipment
CN106408129B (en) * 2016-09-28 2021-05-07 河南中医药大学 Method for detecting quality of traditional Chinese medicine decoction by relative density
CN106265780B (en) * 2016-10-25 2019-12-03 北京汉典制药有限公司 Bilobanone ester dropping pills and preparation method thereof, system
JP7345493B2 (en) * 2018-04-04 2023-09-15 タスリー・ファーマシューティカル・グループ・カンパニー・リミテッド Pharmaceutical compositions and their uses
KR102074067B1 (en) * 2018-05-02 2020-02-06 주식회사 마크로케어 Capsule comprising salvianolic acid and the use of the same
CN109633009A (en) * 2018-12-28 2019-04-16 广西中医药大学 A kind of method of quality control of Radix Salviae Miltiorrhizae and its extract
CN111110689B (en) * 2020-01-13 2021-07-23 吉林修正药业新药开发有限公司 Pharmaceutical composition and pharmaceutical preparation for promoting blood circulation, removing blood stasis, dredging collaterals and relieving pain
EP4144357A4 (en) * 2020-04-29 2024-05-29 Tasly Pharmaceutical Group Co Traditional chinese medicine composition, and application of preparation of traditional chinese medicine composition in preparing medicine for preventing and/or treating coronavirus disease 2019
CN112870216A (en) * 2021-01-29 2021-06-01 张宽才 Pharmaceutical composition, preparation and application

Family Cites Families (92)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3436837A (en) 1963-08-13 1969-04-08 Us Army Fluidized bed freeze drying
GB8509035D0 (en) 1985-04-09 1985-05-15 Pepper D S Preparation of porous bodies
FR2602986A2 (en) 1986-04-10 1988-02-26 Tortochot Gerard Device for cleaning waste disposal, ventilation or sewage pipes
JPS63277616A (en) * 1987-05-09 1988-11-15 Taisho Pharmaceut Co Ltd Production of flavoring oral pharmaceutical
DE4201178C2 (en) 1992-01-17 1995-12-07 Alfatec Pharma Gmbh Process for the production of soft gelatin capsules by a dropping process
US6080429A (en) 1993-10-25 2000-06-27 Genentech, Inc. Method for drying microspheres
EP0799008B1 (en) 1994-12-22 2002-03-20 Kimberly-Clark Worldwide, Inc. Fastening tab
ATE170343T1 (en) 1995-05-04 1998-09-15 Gabo Systemtech Gmbh UNDERFLOOR HOUSING FOR ACCOMMODATION OF ELECTRICAL EQUIPMENT
JP2002104958A (en) 2000-09-29 2002-04-10 Sumitomo Chem Co Ltd Lipophilic vitamin preparation
CN2448361Y (en) 2000-11-02 2001-09-19 傅崇东 Miniature fluidized bed medicine coating machine
UA80393C2 (en) * 2000-12-07 2007-09-25 Алтана Фарма Аг Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix
US8486464B2 (en) * 2000-12-22 2013-07-16 Tasly Pharmaceutical Group Co. Ltd. Herbal composition for angina pectoris, method to prepare same and uses thereof
JP5121038B2 (en) 2000-12-22 2013-01-16 天士力製薬集団股分有限公司 Herbal preparation for angina, method for preparing the herbal preparation and use thereof
CN2508752Y (en) 2001-10-10 2002-09-04 王明川 Steady temperature and constant pressure full automatic machine for making chinese herb medicine pills
JP4429590B2 (en) 2002-02-08 2010-03-10 株式会社協和ウェルネス Ubiquinone-containing water-soluble composition
CN1470255A (en) 2002-07-22 2004-01-28 王智民 Preparation extracted from the root of red-rooted solvia and pseudo-ginseng and its compound preparation and medical use
CN1267111C (en) 2002-12-23 2006-08-02 北京采瑞医药有限公司 Compound red sage drip pill for treating cardiac and cerebral vascular diseases and its prepn process
US20050037094A1 (en) * 2003-07-31 2005-02-17 Xijun Yan Composition for heart disease, its active ingredients, method to prepare same and uses thereof
CN100404040C (en) * 2003-09-19 2008-07-23 天津天士力制药股份有限公司 Medicinal composition for treating cardiopathy and its preparation method and use
CN100339085C (en) 2003-09-23 2007-09-26 天津天士力制药股份有限公司 Combination of Chinese traditional medicine for curing cardiovascular and cerebrovascular diseases
CN100404035C (en) * 2003-09-23 2008-07-23 天津天士力制药股份有限公司 Combination of Chinese traditional medicine for curing cardiovascular diseases and cerebrovascular disease
CN1297288C (en) * 2003-11-19 2007-01-31 王锦刚 Medicine for treating cardiovascular disease, and its prepn. method
CN100563673C (en) 2003-12-11 2009-12-02 天津天士力制药股份有限公司 Chinese medicine preparation of treatment angina pectoris and preparation method thereof
CN2782089Y (en) 2004-02-20 2006-05-24 孙民富 Hot oil conducting circulartion heating constant temp medicinal liquid transffering device of automatic drip bill maker
CN100450501C (en) * 2004-03-17 2009-01-14 天津天士力制药股份有限公司 Chinese medicine preparation for treating cardiovascular and cerebrovascular diseases and preparing process thereof
JP2005306778A (en) 2004-04-21 2005-11-04 Basf Ag Sustained-release formulation and method for producing the same
CN100404041C (en) 2004-06-30 2008-07-23 天津天士力制药股份有限公司 Medicinal composition for treating coronary heart disease
CN1745768B (en) 2004-09-07 2011-03-23 天津天士力制药股份有限公司 Use of medicine containing Milkvetch Root against aspirin
CN1745769A (en) 2004-09-07 2006-03-15 天津天士力制药股份有限公司 Use of medicine composition containing Milkvetch Root
CN100411642C (en) 2004-10-15 2008-08-20 合肥恒星药物研究所 Medication for treating chronic hepatitis
CN1633992A (en) 2004-11-12 2005-07-06 康国忠 Pharmaceutical drop pills and its preparation method
US7727555B2 (en) 2005-03-02 2010-06-01 Boston Scientific Scimed, Inc. Particles
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
CN2794513Y (en) 2005-05-11 2006-07-12 闵金杆 Dripping pill machine
CN1939406A (en) 2005-09-26 2007-04-04 刘凤鸣 Danshen root drop pills for treating coronary heart disease and preparation thereof
EP1774971A1 (en) 2005-10-14 2007-04-18 Advanced in Vitro Cell Technologies, S.L. Chitosan and heparin nanoparticles
CN100335897C (en) 2005-11-02 2007-09-05 中国药科大学 Quality detection method for compound prepn of red sage and notoginseng
CN2873335Y (en) 2005-11-18 2007-02-28 益世环保科技工程(上海)有限公司 Vertical air conditioner pipe cleaner
CN100594021C (en) 2005-12-06 2010-03-17 河北工业大学 Automatic medicinal dropping pill machine
US20070128272A1 (en) 2005-12-07 2007-06-07 Zerbe Horst G Multi-vitamin and mineral supplement
CN2865683Y (en) 2006-01-06 2007-02-07 聊城万合工业制造有限公司 Whole automatic controller for drop pills machine based on PLC control
CN100512830C (en) 2006-05-17 2009-07-15 广州白云山和记黄埔中药有限公司 Pharmaceutical composition for treating senile dementia
EP2020987B1 (en) 2006-06-06 2013-10-30 Universidad Autónoma Metropolitana Sol-gel nanostructured titania reservoirs for use in the controlled release of drugs in the central nervous system and method of synthesis
CN101085000B (en) * 2006-06-08 2012-04-18 天津天士力之骄药业有限公司 Compound red sage root freezing-dried powder injection containing salvianolic acid B and its preparation method
CN101143152B (en) 2006-09-15 2011-07-27 杨明 Dripping pill for treating digestive ulcer and medicine composition containing the same
CN200948597Y (en) 2006-09-25 2007-09-19 湖南大学 Submerged intelligent cleaning robot for large-scale condensing plant
CN100457748C (en) 2006-10-18 2009-02-04 中国医学科学院医药生物技术研究所 Novel phenolic acid compounds of tanshin polyphenolic acid N and application thereof
CN101020028B (en) 2006-11-11 2010-05-19 刘光辉 Chinese medicine for treating cardiac and cerebral vascular diseases
KR20100016167A (en) 2007-04-06 2010-02-12 센주 세이야꾸 가부시키가이샤 Suspension for visualization of transparent tissue in eye
WO2008132707A1 (en) 2007-04-26 2008-11-06 Sigmoid Pharma Limited Manufacture of multiple minicapsules
JP5229606B2 (en) 2007-05-16 2013-07-03 株式会社リコー Toner manufacturing method and toner manufacturing apparatus
CN101439076B (en) 2007-11-22 2012-04-18 天津天士力制药股份有限公司 Preparation method of chinese medicine granule containing dalbergia heartwood oil
CN101229099B (en) 2007-12-28 2011-06-08 天津天士力制药股份有限公司 Equipment for preparing pill using cold wind and trap cooling gas
CN101279220B (en) 2007-12-28 2011-06-08 天津天士力制药股份有限公司 Method for preparing dropping pill using cool air and equipment using the method
CN201200979Y (en) 2008-06-11 2009-03-04 深圳市鑫承诺科技有限公司 Online spraying and cleaning equipment
HUE038785T2 (en) * 2008-07-29 2018-11-28 Hebei Yiling Medicine Res Institute Co Ltd Traditional chinese medicinal composition for the treatment of cardiovascular disease
CN100554840C (en) 2008-08-11 2009-10-28 常州先锋干燥设备有限公司 Vibration fluidization drying system
CN201253349Y (en) 2008-09-25 2009-06-10 高月荣 Ultrasonic atomization method medicine micro-spheres preparation method
CN101711792B8 (en) 2008-10-06 2020-12-22 天士力医药集团股份有限公司 Dripping pill for treating coronary heart disease and preparation method thereof
CN101744722B (en) 2008-12-03 2013-09-11 天士力制药集团股份有限公司 Dripping pill production line
US20100151036A1 (en) 2008-12-16 2010-06-17 Bin Wu Multiphase drug delivery system
CN101757475A (en) * 2008-12-25 2010-06-30 天津药物研究院 Method for preparing fresh snow preparation
CN101518495B (en) * 2009-03-26 2011-12-28 天津大学 Vibration crushing type pill dropping machine
KR20120006029A (en) 2009-03-30 2012-01-17 티안진 타슬리 파마슈티컬 컴퍼니 리미티드 New salvianolic acid compound l, preparation method and use thereof
CN201427125Y (en) 2009-03-31 2010-03-24 王成军 Pipe scale removal robot
CN101584743A (en) * 2009-06-02 2009-11-25 耿福能 Method for preparing Chinese traditional medicinal compound salvia miltiorrhiza preparation for curing cardiovascular and cerebrovascular diseases
CN101612195A (en) 2009-07-17 2009-12-30 江西中医学院 A kind of polynary medicine-releasing system that contains Radix Salviae Miltiorrhizae and Radix Notoginseng
CN102048967A (en) * 2009-11-05 2011-05-11 天津太平洋制药有限公司 Inflammation-diminishing and heat-clearing composition and preparation method thereof
TW201117839A (en) 2009-11-20 2011-06-01 Tianjin Tasly Pharmaceutical Drop pill for treating coronary heart disease and manufacture method thereof
CN102119964B (en) * 2010-01-07 2016-11-23 天津天士力现代中药资源有限公司 A kind of prevention and the extract for the treatment of angina pectoris, their Preparation method and use
CN102119963A (en) 2010-01-07 2011-07-13 天津天士力现代中药资源有限公司 Extract for preventing and treating angina pectoris and coronary heart disease and preparation method and application thereof
CN201589495U (en) 2010-01-18 2010-09-22 山东天力干燥设备有限公司 Multifunctional intermittent drying system of freeze-spray granulation fluidized bed
CN102160872A (en) * 2010-02-23 2011-08-24 天津天士力制药股份有限公司 Compound salvia dropping pill capsules
US8945657B2 (en) 2010-06-22 2015-02-03 The Coca-Cola Company Dehydrated pulp slurry and method of making
AU2011288044B8 (en) 2010-08-06 2014-08-07 Tasly Pharmaceutical Group Co., Ltd. Use of Salvia miltiorrhiza composition in preparing drugs for secondary prevention of coronary heart disease
CN102048707A (en) 2010-11-29 2011-05-11 黑龙江天宏药业有限公司 Mesalazine enteric-coated tablet and preparation method thereof
CN102552256A (en) 2010-12-23 2012-07-11 丽珠医药集团股份有限公司 Ilaprazole enteric capsule and preparation method thereof
CN102078259A (en) 2010-12-29 2011-06-01 天津大学 Equipment and method for preparing uniform dripping pills
CN102178605B (en) 2011-03-09 2014-03-26 天津大学 Traditional Chinese medicine cataplasma forming device with automatic detection function
PT2691415T (en) 2011-03-28 2018-10-19 Ablynx Nv Method for producing solid formulations comprising immunoglobulin single variable domains
CN202027925U (en) 2011-03-29 2011-11-09 中国中医科学院中药研究所 Fully-automatic pill dripping machine with function of online detection
JP2012229173A (en) 2011-04-26 2012-11-22 Ogawa & Co Ltd Vascular endothelial function ameliorating agent
CN102908355B (en) 2011-08-04 2014-06-04 中国科学院上海药物研究所 Medicinal composition and application thereof
CN102526446B (en) * 2012-01-13 2013-11-06 张居运 Traditional Chinese medicine composition for treating coronary heart disease and method for preparing medicated wine by utilizing same
CN102526186A (en) 2012-01-17 2012-07-04 中国中医科学院广安门医院 Medicinal composition for preventing and treating cardiovascular diseases and application thereof
CN102988476A (en) * 2012-08-23 2013-03-27 江苏苏南药业实业有限公司 Method for preparing compound red-rooted salvia root dropping pills
CN104275334A (en) 2013-07-11 2015-01-14 天士力制药集团股份有限公司 On-line cleaning equipment for dropping pill cooling device and cleaning method of on-line cleaning equipment
AU2014289763B2 (en) 2013-07-11 2019-03-07 Tasly Pharmaceutical Group Co., Ltd. Traditional chinese medicine composition, and preparation and application thereof
WO2015003662A1 (en) 2013-07-11 2015-01-15 天士力制药集团股份有限公司 Traditional chinese medicine composition, and preparation and application thereof
CN104418744B (en) 2013-08-29 2017-03-01 天士力制药集团股份有限公司 A kind of new salvianolic acid compound T, Preparation Method And The Use
WO2015027929A1 (en) 2013-08-29 2015-03-05 天士力制药集团股份有限公司 Traditional chinese medicine composition
CN204170103U (en) 2014-07-11 2015-02-25 天士力制药集团股份有限公司 Air cooling dripping pill production line

Also Published As

Publication number Publication date
JP2016526562A (en) 2016-09-05
KR102189849B1 (en) 2020-12-14
TWI631956B (en) 2018-08-11
CA2916963A1 (en) 2015-01-15
EP3020408A1 (en) 2016-05-18
ES2905267T3 (en) 2022-04-07
WO2015003659A9 (en) 2015-02-19
AU2014289763A1 (en) 2016-01-28
US20170157156A9 (en) 2017-06-08
GEP20186877B (en) 2018-07-10
US9999630B2 (en) 2018-06-19
EA034217B1 (en) 2020-01-17
MX2015017697A (en) 2016-08-03
UA118968C2 (en) 2019-04-10
JP7090674B2 (en) 2022-06-24
EP3020408B1 (en) 2022-01-12
EP3020408A4 (en) 2017-03-15
CN104274520B (en) 2018-04-27
CN104274520A (en) 2015-01-14
USRE49035E1 (en) 2022-04-19
JP6906307B2 (en) 2021-07-21
US20160175336A1 (en) 2016-06-23
CA2916963C (en) 2022-11-08
DK3020408T3 (en) 2022-01-31
EA201690207A1 (en) 2016-11-30
JP2020203931A (en) 2020-12-24
KR20160030297A (en) 2016-03-16
HK1220908A1 (en) 2017-05-19
HUE058040T2 (en) 2022-06-28
WO2015003659A1 (en) 2015-01-15
AU2014289763B2 (en) 2019-03-07

Similar Documents

Publication Publication Date Title
TWI621443B (en) Traditional Chinese medicine composition and its use, medicinal preparation containing the traditional Chinese medicine composition and compound salvia miltiorrhiza micro-droplet, and preparation method of the microdroplet
JP7090674B2 (en) Chinese herbal medicine compositions, their formulations and uses
WO2018133563A1 (en) Panax plant extract and pharmaceutical composition and use thereof
KR20230002324A (en) Herbal composition and use of the preparation in the manufacture of a medicament for the prevention and/or treatment of novel coronavirus pneumonia
EP3020395B1 (en) Preparation method for traditional chinese medicine micro drop pill and traditional chinese medicine micro drop pill prepared by using the method
CN101361728B (en) Salvianolic acid A injection and preparation method thereof
CN101721467B (en) Method for preparing total salvianolic acid
CN103520235A (en) Plant composition with lipid-lowering function and preparation method and application thereof